Local delivery of drugs from self assembled coatings

ABSTRACT

The invention relates to oligofluorinated coatings and their use in drag delivery. The oligofluorinated coatings are compositions comprising formula (XVII). These coatings are used in a method of delivering a biologically active agent to a tissue surface in a mammalian tissue. This method occurs by contacting the surface with the coating including an oligofluorinated oligomer and a biologically active agent wherein the coating resides on the tissue surface and release the biologically active agent to the tissue surface.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application No.61/287,862, filed Dec. 18, 2009, which is hereby incorporated byreference.

BACKGROUND OF THE INVENTION

The invention relates to the coalescence of fluorinated oligomers andtherapeutic agents as self assembled coatings and formulations, andtheir use in drug delivery.

Localized therapeutic delivery, including therapies that control theproliferation or growth of tissue into the open path of blood vessels,has been achieved with implantable devices such as drug eluting stents(DES). However, these devices are imperfect and can result in frequentside effects. The presence of residual foreign material can elicit adamaging inflammatory response and induce coagulation. Varioustechniques can be employed to modify the surface of implantable devicesto improve biocompatibility and thromboresistance as well as impartproperties different from those of the device material, e.g., infectionresistance (i.e., via the delivery of a biologically active agent),radiopacity, conductivity, etc. In the DES arena, these techniques havehad limited success.

Transient medical devices, i.e., devices that reside in the body forvery short periods of time (inserted and removed) can also be used aslocalized therapeutic delivery vehicles. The use of a transient medicaldevice (e.g., balloon catheter, guidewire, syringe needle, or probes)would be more advantageous over permanent, implantable medical devicesas there are no long term biocompatibility issues.

As a result of the issues associated with DES, the concept of using adrug eluting balloon (DEB) catheter to locally deliver ananti-restenotic drug, such as paclitaxel, at the site of arterialdisease is now seen as an opportunity to provide an alternativetreatment which circumvents many of the concerns associated with DES.The DEB catheter would deliver a therapeutic amount of drug effectivelyupon inflation while in contact with the lumen wall for a limited time.

The DEB catheter approach has been the subject of several clinicaltrials since 2006. However, the outcome of many of these trials,including several repeated by the same companies with slightlyreformulated materials, has been one of limited successes, due toinherent limitations in the carrier molecules for the drugs. The generalstrategy has been to coat the balloon catheter with established dyeagents or pharmaceutical emulsifying materials that have an establishedregulatory history (see U.S. Patent Publication No. 20060020243). Theresult is a less than optimal performance in terms of retention onto theballoon during intra-luminal delivery (e.g., 90% of drug can be losteven before reaching the targeted tissues, with some absorbed into theballoons, and <6% being transferred to the diseased tissue) (see Axel DeLabriolle et al., Catheterization and Cardiovascular Interventions73:643 (2009)).

These results demonstrate a need for a synthetic modular approach toaddress the limitations of drug retention with efficient andpreferential transfer of drug into the local tissues. To address theseimitations, the carrier molecule needs to be designed with low bloodactivation with reduced local delivery of the carrier system uponarrival of the balloon at the target site.

SUMMARY OF THE INVENTION

The methods and compositions of the invention feature branchedoligomeric compounds (e.g., oligofluorinated coatings and formulations),and their use in drug delivery.

In a first aspect, the invention features a composition of formula

where

m and n are both 0, or m and n are both 1;

each A and A₂ is a trifunctional monomer having a molecular weightbetween 50-3500 Da;

each L and L_(A) is, independently, a linker;

each R_(X1A), R_(X1B), R_(X2A), and R_(X2B) is, independently, a waterinsoluble segment having a molecular weight between 200-3,500 Da; and

R_(Y1) is a non-halogenated organic segment having a molecular weightbetween 200-3,500 Da; and

when m and n are both 1, each of R_(Z1) and R_(Z2) is, independently, adifunctional water insoluble segment having a molecular weight between50-3,500 Da, or

when m and n are both 0, each of R_(Z1) and R_(Z2) is, independently awater insoluble segment having a molecular weight between 200-3,500 Da.

In some embodiments, the composition has the following formula

where

A is a trifunctional monomer having a molecular weight between 50-3500Da; each L is, independently, a linker;

R_(Z1) and R_(Z2) are each, independently, a water insoluble segment(e.g., an organohalide segment) having a molecular weight between200-3,500 Da; and

R_(Y1) is a non-halogenated organic segment having a molecular weightbetween 100-3,500 Da.

In some embodiments, A is a trifunctional monomer having a molecularweight between 50-1000 Da; each L is, independently, a linker; R_(Z1)and R_(Z2) are each, independently, water insoluble segments such as anorganohalide segment having a molecular weight between 200-3,500 Da; andR_(Y1) is a non-halogenated organic segment having a molecular weightbetween 100-3,500 Da.

In other embodiments, the composition is described by the followingformula (XV-B):

In other embodiments, the composition has the following formula

where

each A and A₂ is a trifunctional monomer having a molecular weightbetween 50-3500 Da; each L and L_(A) is, independently, a linker; eachR_(X1A), R_(X1B), R_(X2A), and R_(X2B) are each, independently, a waterinsoluble segment having a molecular weight between 200-3,500 Da; andR_(Y1) is a non-halogenated organic segment having a molecular weightbetween 100-3,500 Da, and each R_(Z1) is, independently, a difunctionalwater insoluble segment having a molecular weight between 100-3,500 Da.In some embodiments, R_(Z1) is a fluorinated diol. It would beunderstood by those skilled in the art that the R-like branches could beincreased to further generations of the branching. Likewise it would beunderstood by those skilled in the art that the R_(Y1) moiety could alsohave branching segments if desired. In some embodiments, A includes atriol.

In other embodiments, A includes a glycerol, trimethylolpropane (TMP),trimethylolethane (TME), trimesic acid (TMA), ortris(hydroxyethyl)isocyanurate (THEIC).

In any of the above formulas, R_(Y1) may be branched or unbranched.

In certain embodiments, R_(Y1) is a linear or branched polyethyleneglycol, zwitterions (including zwitterionic surfactant moieties, e.g.,alkyl betaines, such as alkyl amidopropyl betaine, sulfobetaines andalkyl sultaines, alkyl ether hydroxyl propyl sultaines, andalkylamidopropylhydroxy sultaines), or polyvinylpyrrolidone.

In other embodiments, R_(Z1) and R_(Z2) are each, independently, apolyfluoroorgano, a polysiloxane, or polyolefin group, or wherein eachof R_(X1A), R_(X1B), R_(X2A), R_(X2B) are each, independently, apolyfluoroorgano, a polysiloxane, or polyolefin group.

In still other embodiments, R_(Z1) and R_(Z2) are each, independently, asilicone group, or wherein each of R_(X1A), R_(X1B), R_(X2A), R_(X2B)are each, independently, a silicone group.

In other embodiments, the composition is described by the followingformula,

where F_(T) is a polyfluoroorgano group; L is a linker; X₁ is H, CH₃, orCH₂CH₃;

X₂ is H, CH₃, or CH₂CH₃; and n is an integer from 5 to 50.

In any of the embodiments described herein, the linker is described byformula (XVI):

G¹-(Z¹)_(o)—(Y¹)_(u)—(Z²)_(s)—(R₁₀)—(Z³)_(t)—(Y²)_(v)—(Z⁴)_(p)-G²  (XVI)

where

G¹ is a bond between said polyfluoroorgano group and said linker;

G² is a bond between said linker and an oxygen atom;

Z¹, Z², Z³, and Z⁴ each, independently, is selected from O, S, and NR₁₁;

R₁₁ is hydrogen or a C₁₋₁₀ alkyl group;

Y¹ and Y² are each, independently, selected from carbonyl, thiocarbonyl,sulphonyl, or phosphoryl;

o, p, s, t, u, and v are each, independently, 0 or 1; and

R₁₀ is a substituted or unsubstituted C₁₋₁₀ alkyl, a heteroalkyl of 1 to10 atoms, a C₂₋₁₀ alkene, a C₂₋₁₀ alkyne, a C₅₋₁₀ aryl, a cyclic systemof 3 to 10 atoms, —(CH₂CH₂O)_(q)CH₂CH₂— in which q is an integer of 1 to10, or a chemical bond linking G¹-(Z¹)_(o)—(Y¹)_(u)—(Z²)_(s)— to—(Z³)_(t)—(Y²)_(v)—(Z⁴)_(p)-G².

In some embodiments, the linker is a covalent bond or a —(C═O)— group.

In some embodiments, the composition is described by formula (XVII):

where F_(T) is a polyfluoroorgano group; L₂ is a substituted orunsubstituted C₁₋₁₀ alkyl, a heteroalkyl of 1 to 10 atoms, a C₂₋₁₀alkene, a C₂₋₁₀ alkyne, a C₅₋₁₀ aryl, a cyclic system of 3 to 10 atoms,—(CH₂CH₂O)_(q)CH₂CH₂— in which q is an integer of 1 to 10; X₁ is H, CH₃,or CH₂CH₃; X₂ is H, CH₃, or CH₂CH₃; and n is an integer from 5 to 50.

In some embodiments, the polyfluoroorgano group is a polyfluoroalkylhaving a molecular weight of between 100-1,500 Da.

In other embodiments, the polyfluoroorgano group is a radical of thegeneral formula CF₃(CF₂)_(r)CH₂CH₂— or CF₃(CF₂)_(s)(CH₂CH₂O)_(χ)—,wherein r is an integer from 2-20, χ is an integer from 1-10, and s isan integer from 1-20.

In still other embodiments, the polyfluoroorgano group is a radical ofthe general formula CH_(m)F_((3-m))(CF₂)_(r)CH₂CH₂— orCH_(m)F_((3-m))(CF₂)_(s)(CH₂CH₂O)_(χ)—, wherein m is 0, 1, 2, or 3; χ isan integer between 1-10; r is an integer between 2-20; and s is aninteger between 1-20.

In certain embodiments, the polyfluoroorgano group is selected from(CF₃)(CF₂)₅CH₂CH₂O—, (CF₃)(CF₂)₇CH₂CH₂O—, (CF₃)(CF₂)₅CH₂CH₂O—,CHF₂(CF₂)₃CH₂O—, and (CF₃)(CF₂)₂CH₂O—, 1H,1H,2H,2H-perfluoro-1-decanol;1H,1H,2H,2H-perfluoro-1-octanol; 1H,1H,5H-perfluoro-1-pentanol; and1H,1H, perfluoro-1-butanol, and mixtures thereof.

In some embodiments, the composition includes a mixture of (i) any ofthe compositions described herein (for example, an oligofluorinatedoligomer (e.g., a branched or linear oligofluorinated oligomer) or abranched compound including water insoluble segments); and (ii) a drug.In some embodiments, the drug is a hydrophobic drug (e.g., the drug isselected from antiproliferative agents and rapamycin macrolides). Insome embodiments, the hydrophobic drug is an antiproliferative agentselected from methotrexate, trimetrexate, gemcitabine, vinblastine,vincristine, etoposide, teniposide, topotecan, irinotecan, camptothecin,9-aminocamptothecin, paclitaxel, docetaxel, daunorubicin, doxorubicin,dactinomycin, idarubincin, bleomycin, and tamoxifen. In otherembodiments, the hydrophobic drug is a rapamycin macrolide selected fromrapamycin, CCI-779, Everolimus, and ABT-578. In other embodiments, thehydrophobic drug is paclitaxel. In some embodiments, (i):(ii) are in aratio of 20:1 to 1:20.

In certain embodiments, the coating includes an oligofluorinatedoligomer. The oligofluorinated oligomer can be a compound of any ofFormulas (I)-(VIII), optionally having an average molecular weight offrom 2 kDa to 50 KDa (e.g., from 2 kDa to 5 KDa, 4 kDa to 12 KDa, 6 kDato 15 KDa, 5 kDa to 25 KDa, 3 kDa to 20 KDa, or from 10 kDa to 50 KDa.In certain embodiments, the oligofluorinated oligomer is a compound offormula (I), (III), (IV), (V), or (VI). The oligofluorinated oligomercan be a grafted polymer of Formula (IX). Alternatively, theoligofluorinated oligomer can be a cross linked polymer of any ofFormulas (X)-(XIV). In other embodiments, the coating includes abranched compound including water insoluble segments. The branchedcompound can be a compound of any of Formulas (XV), (XV-A), (XV-B),(XV-C), or (XVII), optionally having an average molecular weight of from1 kDa to 50 KDa (e.g., from 1 kDa to 5 KDa, 3 kDa to 12 KDa, 6 kDa to 15KDa, 5 kDa to 25 KDa, 12 kDa to 40 KDa, or from 15 kDa to 50 KDa.

In any of the embodiments described herein, the composition furtherincludes water. In some embodiments, the composition is an aqueousdispersion (e.g., a single or two phase dispersion).

In other embodiments, the composition is a solid dispersion.

In still other embodiments, the composition is suitable for systemicinjection.

In some embodiments, the composition is in the form of liquid, tablets,capsule, powder, injectable and suppositories.

In some embodiments, the solubility of the hydrophobic drug isincreased.

Any of the compositions described herein can be used in any of themethods or transient medical devices described herein.

In another aspect, the invention features a method of delivering abiologically active agent to a tissue surface in a mammalian tissue bycontacting the surface with a self assembling coating including (i) anoligofluorinated oligomer (e.g., a branched or linear oligofluorinatedoligomer) or a branched compound including water insoluble segments and(ii) a biologically active agent, wherein the self assembling coatingresides on the tissue surface in the absence of an implanted medicaldevice following the contacting and releases the biologically activeagent to the tissue surface.

In certain embodiments, the coating includes an oligofluorinatedoligomer. The oligofluorinated oligomer can be a compound of any ofFormulas (I)-(VIII), optionally having an average molecular weight offrom 2 kDa to 50 KDa (e.g., from 2 kDa to 5 KDa, 4 kDa to 12 KDa, 6 kDato 15 KDa, 5 kDa to 25 KDa, 3 kDa to 20 KDa, or from 10 kDa to 50 KDa.In certain embodiments, the oligofluorinated oligomer is a compound offormula (I), (III), (IV), (V), or (VI). The oligofluorinated oligomercan be a grafted polymer of Formula (IX). Alternatively, theoligofluorinated oligomer can be a cross linked polymer of any ofFormulas (X)-(XIV). In other embodiments, the coating includes abranched compound including water insoluble segments. The branchedcompound including water insoluble segments can be a compound of any ofFormulas (XV), (XV-A), (XV-B), (XV-C), or (XVII), optionally having anaverage molecular weight of from 1 kDa to 50 KDa (e.g., from 1 kDa to 5KDa, 3 kDa to 12 KDa, 6 kDa to 15 KDa, 5 kDa to 25 KDa, 12 kDa to 40KDa, or from 15 kDa to 50 KDa.

The invention also features a method of delivering a biologically activeagent to a tissue surface in a mammalian tissue by contacting thesurface with a transient medical device coated with a self assemblingcoating, the self assembling coating including (i) an oligofluorinatedoligomer (e.g., a branched or linear oligofluorinated oligomer) orbranched compound including water insoluble segments and (ii) abiologically active agent, wherein the transient medical device, uponthe contacting, releases the biologically active agent to the tissuesurface. In certain embodiments, the transient medical device is capableof disruption of the self assembling coating and, upon the disruption,releases the biologically active agent to the tissue surface. Forexample, the transient medical device can be a deformable transientmedical device which, upon being deployed into a deformed configuration,mechanically disrupts the self assembling coating and releases thebiologically active agent to the tissue surface. Alternatively, thetransient medical device can be configured to direct a source of energyat the self assembling coating to disrupt the self assembling coating inresponse to the energy (e.g., ultrasound, heat, electromagnetic, orvibrational energy). The self assembling coating can be applied to thesurface of the transient medical device by solid deposition, spraycoating, printing, or dip coating. For example, the self assemblingcoating can be applied to the surface of the device in a two stepapproach; first the device is coated with the oligofluorinated oligomer(e.g., a branched or linear oligofluorinated oligomer) or branchedcompound including water insoluble segments and second with thebiologically active agent. In some embodiments the oligofluorinatedoligomer of the self assembling coating forms a self assembled layer onthe transient medical device. The coating can have a thickness of from0.01 to 250 microns (e.g., from 0.01 to 5 microns, 0.1 to 5 microns, 1to 5 microns, 1 to 25 microns, 2 to 25 microns, 5 to 50 microns, 5 to100 microns, 10 to 250 microns, 15 to 50 microns, or 20 to 125 microns).In particular embodiments from 5 to 55% (w/w) of the biologically activeagent can be delivered from the transient medical device to themammalian tissue (e.g., from 5 to 35%, 15 to 85%, 20 to 95%, 25 to 65%,25 to 85%, 35 to 65%, 35 to 95%, 40 to 95%, or from 55 to 95% (w/w) ofthe biologically active agent is delivered). In certain embodiments thatthe tissue surface is in a blood vessel, the self assembling coatingcoats a surface of a transient medical device, and from 25 to 85% (w/w)of the biologically active agent is retained on the medical device priorto delivery to the tissue surface (e.g., from 25 to 75%, 25 to 65%, 35to 95%, 35 to 75%, 45 to 95%, 45 to 75%, 55 to 95%, or from 55 75% (w/w)of the biologically active agent is retained). In still otherembodiments, the transient medical device is folded upon itself, andfrom 25 to 85% (w/w) of the biologically active agent is retained on themedical device upon deploying the transient medical device from a foldedto an unfolded configuration (e.g., from 25 to 75%, 25 to 65%, 35 to95%, 35 to 75%, 45 to 95%, 45 to 75%, 55 to 95%, or from 55 75% (w/w) ofthe biologically active agent is retained).

In certain embodiments of the above aspects, the tissue surface is aluminal system of the mammalian tissue (e.g., a blood vessel, a veingraft, a synthetic graft, or a lumen in the respiratory, urinary,reproductive, neurologic or digestive systems). For example, the selfassembling coating can be applied to the surface of a balloon catheter,inserted into a luminal system of the mammalian tissue, and deployedinto an expanded configuration to transfer the biologically active agentfrom the surface of the balloon catheter to a tissue surface of theluminal system.

In any of the above aspects, the oligofluorinated oligomer (e.g., abranched or linear oligofluorinated oligomer) or the branched compoundincluding water insoluble segments of the self assembling coating can beresorbable or non-resorbable. In certain embodiments, the coatingincludes an oligofluorinated oligomer. The oligofluorinated oligomer canbe a compound of any of Formulas (I)-(VIII), optionally having anaverage molecular weight of from 2 kDa to 50 KDa (e.g., from 2 kDa to 5KDa, 4 kDa to 12 KDa, 6 kDa to 15 KDa, 5 kDa to 25 KDa, 3 kDa to 20 KDa,or from 10 kDa to 50 KDa. In certain embodiments, the oligofluorinatedoligomer is a compound of formula (I), (III), (IV), (V), or (VI). Theoligofluorinated oligomer can be a grafted polymer of Formula (IX).Alternatively, the oligofluorinated oligomer can be a cross linkedpolymer of any of Formulas (X)-(XIV). In other embodiments, the coatingincludes a branched compound including water insoluble segments. Thebranched compound can be a compound of any of Formulas (XV), (XV-A),(XV-B), (XV-C), or (XVII), optionally having an average molecular weightof from 1 kDa to 50 KDa (e.g., from 1 kDa to 5 KDa, 3 kDa to 12 KDa, 6kDa to 15 KDa, 5 kDa to 25 KDa, 12 kDa to 40 KDa, or from 15 kDa to 50KDa.

In certain embodiments of the above aspects, the self assembling coatingconsists of components having a molecular weight of from 1 kDa to 60 kDa(e.g., from 1 kDa to 40 kDa, 2 kDa to 60 kDa, 2 kDa to 40 kDa, 3 kDa to60 kDa, 3 kDa to 40 kDa, 5 kDa to 60 kDa, 5 kDa to 40 kDa, 10 kDa to 60kDa, or from 15 kDa to 60 kDa).

In still other embodiments of the above aspects, the oligofluorinatedoligomer (e.g., a branched or linear oligofluorinated oligomer) orbranched compound including water insoluble segments has a theoreticalmolecular weight of from 1 kDa to 30 kDa (e.g., from 1 kDa to 60 kDa, 2kDa to 60 kDa, 2 kDa to 30 kDa, 3 kDa to 60 kDa, 3 kDa to 30 kDa, 5 kDato 60 kDa, 5 kDa to 30 kDa, 10 kDa to 60 kDa, or from 10 kDa to 30 kDa).

In particular embodiments of the above aspects, the oligofluorinatedoligomer includes a hard segment, a soft segment, and polyfluoroorganogroup, wherein the oligofluorinated oligomer includes from 5 to 80%(w/w) of the hard segment, from 10 to 90% (w/w) of the soft segment, andfrom 5 to 80% (w/w) of the polyfluoroorgano group.

In any of the above aspects, the biologically active agent can beuniformly distributed throughout the self assembling coating. In certainembodiments, the coating includes an oligofluorinated oligomer. Theoligofluorinated oligomer can be a compound of any of Formulas(I)-(VIII), optionally having an average molecular weight of from 2 kDato 50 KDa (e.g., from 2 kDa to 5 KDa, 4 kDa to 12 KDa, 6 kDa to 15 KDa,5 kDa to 25 KDa, 3 kDa to 20 KDa, or from 10 kDa to 50 KDa. In certainembodiments, the oligofluorinated oligomer is a compound of formula (I),(III), (IV), (V), or (VI). The oligofluorinated oligomer can be agrafted polymer of Formula (IX). Alternatively, the oligofluorinatedoligomer can be a cross linked polymer of any of Formulas (X)-(XIV). Inother embodiments, the coating includes a branched compound includingwater insoluble segments. The branched compound can be a compound of anyof Formulas (XV), (XV-A), (XV-B), (XV-C), or (XVII), optionally havingan average molecular weight of from 1 kDa to 50 KDa (e.g., from 1 kDa to5 KDa, 3 kDa to 12 KDa, 6 kDa to 15 KDa, 5 kDa to 25 KDa, 12 kDa to 40KDa, or from 15 kDa to 50 KDa.

In any of the above aspects, the self assembling coating can includefrom 1 to 30% (w/w) fluorine atoms (e.g., from 2 to 30%, 3 to 30%, 4 to30%, 5 to 30%, 2 to 10%, 3 to 15%, or 4 to 20% (w/w) fluorine atoms).

In any of the above aspects, the self assembling coating includes from0.1 to 50% (w/w) biologically active agent (e.g., from 0.1 to 10%, 0.5to 30%, 1 to 50%, 2 to 50%, 2 to 30%, 3 to 50%, 0.5 to 5%, 0.5 to 10%, 1to 10%, 2 to 15%, 2 to 25%, 3 to 15%, or 3 to 25% (w/w) biologicallyactive agent).

In any of the above aspects, the self assembling coating can include amolar ratio of oligofluorinated oligomer (e.g., a branched or linearoligofluorinated oligomer) or branched compound including waterinsoluble segments to biologically active agent of from 20:1 to 1:20(e.g., from 1:1 to 1:20, 20:1 to 1:1, 10:1 to 1:10, 1:1 to 1:10, 10:1 to1:1, 5:1 to 1:5, 1:1 to 1:5, or 5:1 to 1:1). In certain embodiments, thecoating includes an oligofluorinated oligomer. The oligofluorinatedoligomer can be a compound of any of Formulas (I)-(VIII), optionallyhaving an average molecular weight of from 2 kDa to 50 KDa (e.g., from 2kDa to 5 KDa, 4 kDa to 12 KDa, 6 kDa to 15 KDa, 5 kDa to 25 KDa, 3 kDato 20 KDa, or from 10 kDa to 50 KDa. In certain embodiments, theoligofluorinated oligomer is a compound of formula (I), (III), (IV),(V), or (VI). The oligofluorinated oligomer can be a grafted polymer ofFormula (IX). Alternatively, the oligofluorinated oligomer can be across linked polymer of any of Formulas (X)-(XIV). In other embodiments,the coating includes a branched compound including water insolublesegments. The branched compound can be a compound of any of Formulas(XV), (XV-A), (XV-B), (XV-C), or (XVII), optionally having an averagemolecular weight of from 1 kDa to 50 KDa (e.g., from 1 kDa to 5 KDa, 3kDa to 12 KDa, 6 kDa to 15 KDa, 5 kDa to 25 KDa, 12 kDa to 40 KDa, orfrom 15 kDa to 50 KDa.

In any of the above aspects, the self assembling coating can have aglass transition of from −80 to 40° C. (e.g., from −80 to 5° C., −60 to5° C., −50 to 20° C., −40 to 30° C., −30 to 40° C., −20 to 40° C., or−15 to 25° C.).

In any of the above aspects, the self assembling coating can have a tackof from 1.0 to 200 g (e.g., from 1.0 to 100 g, 1.0 to 50 g, 2.0 to 200g, 2.0 to 100 g, 2.0 to 50 g 1.0 to 25 g, 2.0 to 25 g, 3.0 to 75 g, 3.0to 50 g, 3.0 to 25 g, or 1.0 to 20 g).

In any of the above aspects, the self assembling coating can have aviscosity of from 0.04 to 130 cps (e.g., from 20 to 130 cps, 50 to 130cps, 75 to 130 cps, 0.04 to 30 cps, 0.04 to 70 cps, 0.5 to 130 cps, 0.5to 13 cps, 0.5 to 30 cps, 0.5 to 70 cps, 1 to 130 cps, 1 to 20 cps, 1 to50 cps, 5 to 25 cps, or 5 to 75 cps).

In any of the above aspects, the self assembling coating can have acontact angle hysteresis of the surface of from 20-120° (e.g., from20-60°, 30-70°, 40-80°, 60-90°, 70-100°, 80-110°, 90-120°, 60-120°, or35-90°).

In any of the above aspects, the biologically active agent within thecoating can have a dissociation constant in phosphate buffered saline offrom to 1% to 99% (e.g., from 1% to 85%, 5% to 99%, 5% to 85%, 10% to99%, 10% 25 to 85%, 20% to 99%, 20% to 85%, 30% to 99%, 30% to 85%, 40%to 99%, or 50% to 99%).

In any of the above aspects, the biologically active agent can beselected from proteins, peptides, carbohydrates, antibiotics,antiproliferative agents, rapamycin macrolides, analgesics, anesthetics,antiangiogenic agents, antithrombotic agents, vasoactive agents,anticoagulants, immunomodulators, cytotoxic agents, antiviral agents,antibodies, neurotransmitters, psychoactive drugs, oligonucleotides,vitamins, lipids, and prodrugs thereof. In particular embodiments, thebiologically active agent is selected from antiproliferative agents(e.g., methotrexate, trimetrexate, gemcitabine, vinblastine,vincristine, etoposide, teniposide, topotecan, irinotecan, camptothecin,9-aminocamptothecin, paclitaxel, docetaxel, daunorubicin, doxorubicin,dactinomycin, idarubincin, bleomycin, and tamoxifen) and rapamycinmacrolides (e.g., rapamycin, CCI-779, Everolimus, and ABT-578). Theseagents can be useful, for example, where the tissue surface is a vesselwall and the therapy is delivered to inhibit restenosis of the vessel.

In any of the above aspects, the self assembling coating can beexcretable.

In any of the above aspects, the mammalian tissue can be in a subject.

In a related aspect, the invention features a transient medical devicehaving a surface with a self assembling coating deposited thereon, theself assembling coating including (i) an oligofluorinated oligomer(e.g., a branched or linear oligofluorinated oligomer) or branchedcompound including water insoluble segments and (ii) a biologicallyactive agent, wherein the transient medical device includes an energygenerating element, the energy generating element being capable ofdisrupting the self assembling coating when activated. For example, theenergy generating element can generate ultrasound, heat,electromagnetic, or vibrational energy.

In certain embodiments, the coating includes an oligofluorinatedoligomer. The oligofluorinated oligomer can be a compound of any ofFormulas (I)-(VIII), optionally having an average molecular weight offrom 2 kDa to 50 KDa (e.g., from 2 kDa to 5 KDa, 4 kDa to 12 KDa, 6 kDato 15 KDa, 5 kDa to 25 KDa, 3 kDa to 20 KDa, or from 10 kDa to 50 KDa.In certain embodiments, the oligofluorinated oligomer is a compound offormula (I), (III), (IV), (V), or (VI). The oligofluorinated oligomercan be a grafted polymer of Formula (IX). Alternatively, theoligofluorinated oligomer can be a cross linked polymer of any ofFormulas (X)-(XIV). In other embodiments, the coating includes abranched compound including water insoluble segments. The branchedcompound can be a compound of any of Formulas (XV), (XV-A), (XV-B),(XV-C), or (XVII), optionally having an average molecular weight of from1 kDa to 50 KDa (e.g., from 1 kDa to 5 KDa, 3 kDa to 12 KDa, 6 kDa to 15KDa, 5 kDa to 25 KDa, 12 kDa to 40 KDa, or from 15 kDa to 50 KDa.

The invention further features a transient medical device having asurface with a self assembling coating deposited thereon, the selfassembling coating including (i) an oligofluorinated oligomer (e.g., abranched or linear oligofluorinated oligomer) or branched compoundincluding water insoluble segments and (ii) a biologically active agent,wherein the transient medical device is a deformable transient medicaldevice which, upon being deployed into a deformed configuration,mechanically disrupts the self assembling coating. For example, thedeformable transient medical device can be a balloon catheter.

In certain embodiments, the coating includes an oligofluorinatedoligomer. The oligofluorinated oligomer can be a compound of any ofFormulas (I)-(VIII), optionally having an average molecular weight offrom 2 kDa to 50 KDa (e.g., from 2 kDa to 5 KDa, 4 kDa to 12 KDa, 6 kDato 15 KDa, 5 kDa to 25 KDa, 3 kDa to 20 KDa, or from 10 kDa to 50 KDa.In certain embodiments, the oligofluorinated oligomer is a compound offormula (I), (III), (IV), (V), or (VI). The oligofluorinated oligomercan be a grafted polymer of Formula (IX). Alternatively, theoligofluorinated oligomer can be a cross linked polymer of any ofFormulas (X)-(XIV). In other embodiments, the coating includes abranched compound including water insoluble segments. The branchedcompound can be a compound of any of Formulas (XV), (XV-A), (XV-B),(XV-C), or (XVII), optionally having an average molecular weight of from1 kDa to 50 KDa (e.g., from 1 kDa to 5 KDa, 3 kDa to 12 KDa, 6 kDa to 15KDa, 5 kDa to 25 KDa, 12 kDa to 40 KDa, or from 15 kDa to 50 KDa.

In any of the above transient medical devices, the coating can have athickness of from 0.01 to 250 microns (e.g., from 0.01 to 5 microns, 0.1to 5 microns, 1 to 5 microns, 1 to 25 microns, 2 to 25 microns, 5 to 50microns, 5 to 100 microns, 10 to 250 microns, 15 to 50 microns, or 20 to125 microns).

In certain embodiments of the above transient medical devices, the selfassembling coating consists of components having a molecular weight offrom 1 kDa to 60 kDa (e.g., from 1 kDa to 40 kDa, 2 kDa to 60 kDa, 2 kDato 40 kDa, 3 kDa to 60 kDa, 3 kDa to 40 kDa, 5 kDa to 60 kDa, 5 kDa to40 kDa, 10 kDa to 60 kDa, or from 15 kDa to 60 kDa).

In still other embodiments of the above transient medical devices, theoligofluorinated oligomer (e.g., a branched or linear oligofluorinatedoligomer) or branched compound including water insoluble segments has atheoretical molecular weight of from 1 kDa to 30 kDa (e.g., from 1 kDato 60 kDa, 2 kDa to 60 kDa, 2 kDa to 30 kDa, 3 kDa to 60 kDa, 3 kDa to30 kDa, 5 kDa to 60 kDa, 5 kDa to 30 kDa, 10 kDa to 60 kDa, or from 10kDa to 30 kDa).

In particular embodiments of the above transient medical devices, theoligofluorinated oligomer (e.g., a branched or linear oligofluorinatedoligomer) or branched compound including water insoluble segmentsincludes a hard segment, a soft segment, and polyfluoroorgano group,wherein the oligofluorinated oligomer includes from 5 to 80% (w/w) ofthe hard segment, from 10 to 90% (w/w) of the soft segment, and from 5to 80% (w/w) of the polyfluoroorgano group.

In any of the above transient medical devices, the biologically activeagent can be uniformly distributed throughout the self assemblingcoating.

In any of the above transient medical devices, the biologically activeagent can be incorporated into the self assembling coating by soliddeposition method.

In any of the above transient medical devices, the self assemblingcoating can include from 1 to 30% (w/w) fluorine atoms (e.g., from 2 to30%, 3 to 30%, 4 to 30%, 5 to 30%, 2 to 10%, 3 to 15%, or 4 to 20% (w/w)fluorine atoms).

In any of the above transient medical devices, the self assemblingcoating includes from 0.1 to 50% (w/w) biologically active agent (e.g.,from 0.1 to 10%, 0.5 to 30%, 1 to 50%, 2 to 50%, 2 to 30%, 3 to 50%, 0.5to 5%, 0.5 to 10%, 1 to 10%, 2 to 15%, 2 to 25%, 3 to 15%, or 3 to 25%(w/w) biologically active agent).

In any of the above transient medical devices, the self assemblingcoating can include a molar ratio of oligofluorinated oligomer (e.g., abranched or linear oligofluorinated oligomer) or branched compoundincluding water insoluble segments to biologically active agent of from20:1 to 1:20 (e.g., from 1:1 to 1:20, 20:1 to 1:1, 10:1 to 1:10, 1:1 to1:10, 10:1 to 1:1, 5:1 to 1:5, 1:1 to 1:5, or 5:1 to 1:1).

In any of the above transient medical devices, the self assemblingcoating can have a glass transition of from −80 to 40° C. (e.g., from−80 to 5° C., −60 to 5° C., −50 to 20° C., −40 to 30° C., −30 to 40° C.,−20 to 40° C., or −15 to 25° C.).

In any of the above transient medical devices, the self assemblingcoating can have a tack of from 1.0 to 200 g (e.g., from 1.0 to 100 g,1.0 to 50 g, 2.0 to 200 g, 2.0 to 100 g, 2.0 to 50 g, 1.0 to 25 g, 2.0to 25 g, 3.0 to 75 g, 3.0 to 50 g, 3.0 to 25 g, or 1.0 to 20 g).

In any of the above transient medical devices, the self assemblingcoating can have a viscosity of from 0.04 to 130 cps (e.g., from 20 to130 cps, 50 to 130 cps, 75 to 130 cps, 0.04 to 30 cps, 0.04 to 70 cps,0.5 to 130 cps, 0.5 to 13 cps, 0.5 to 30 cps, 0.5 to 70 cps, 1 to 130cps, 1 to 20 cps, 1 to 50 cps, 5 to 25 cps, or 5 to 75 cps).

In any of the above transient medical devices, the self assemblingcoating can have a contact angle hysteresis of the surface of from20-120° (e.g., from 20-60°, 30-70°, 40-80°, 60-90°, 70-100°, 80-110°,90-120°, 60-120°, or 35-90°).

In any of the above transient medical devices, the biologically activeagent can be selected from proteins, peptides, carbohydrates,antibiotics, antiproliferative agents, rapamycin macrolides, analgesics,anesthetics, antiangiogenic agents, antithrombotic agents, vasoactiveagents, anticoagulants, immunomodulators, cytotoxic agents, antiviralagents, antibodies, neurotransmitters, psychoactive drugs,oligonucleotides, vitamins, lipids, and prodrugs thereof. In particularembodiments, the biologically active agent is selected fromantiproliferative agents (e.g., methotrexate, trimetrexate, gemcitabine,vinblastine, vincristine, etoposide, teniposide, topotecan, irinotecan,camptothecin, 9-aminocamptothecin, paclitaxel, docetaxel, daunorubicin,doxorubicin, dactinomycin, idarubincin, bleomycin, and tamoxifen) andrapamycin macrolides (e.g., rapamycin, CCI-779, Everolimus, andABT-578).

In any of the above transient medical devices, the self assemblingcoating can be excretable.

The invention further features a method for delivering a biologicallyactive agent to a site in a vessel by including inserting into thevessel a transient medical device of the invention, positioning thetransient medical device near the site, and disrupting the coating onthe transient medical device deliver the biologically active agent tothe site.

The invention features a method for inhibiting restenosis at a site in avessel by inserting into the vessel a transient medical including anenergy generating element and activating the energy generating element,wherein the biologically active agent is selected from antiproliferativeagents and rapamycin macrolides.

The invention also features a method for inhibiting restenosis at a sitein a vessel by inserting into the vessel a deformable transient medicaldevice of the invention, and deploying the deformable transient medicaldevice into a deformed configuration, wherein the biologically activeagent is selected from antiproliferative agents and rapamycinmacrolides. In certain embodiments, the deformable transient medicaldevice is a catheter balloon. The method can further include deploying astent at the site of disease (e.g., a stent can be deployed prior to thedeployment of the catheter balloon, or deployed after deployment of thecatheter balloon). The catheter balloon can be deployed for thetreatment of in-stent-restenosis.

In any of the above methods for treating a vessel, the vessel can be abifurcated vessel.

The tack of a coating of the invention can be measured, for example,using a TA.XTPlus Texture Analyser (Stable Micro Systems; distributed byTexture Technologies Corp; Scarsdale, N.Y.), which measures tack in“grams of force”.

By “C₁₋₁₀ alkyl” is meant a branched or unbranched saturated hydrocarbongroup, having 1 to 10 carbon atoms, inclusive. An alkyl may optionallyinclude monocyclic, bicyclic, or tricyclic rings, in which each ringdesirably has three to six members. The alkyl group may be substitutedor unsubstituted. Exemplary substituents include alkoxy, aryloxy,sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl,perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino,hydroxyalkyl; carboxyalkyl, and carboxyl groups.

By “C₂₋₁₀ alkene” is meant a branched or unbranched hydrocarbon groupcontaining one or more double bonds, desirably having from 2 to 10carbon atoms. A C₂₋₁₀ alkene may optionally include monocyclic,bicyclic, or tricyclic rings, in which each ring desirably has five orsix members. The C₂₋₁₀ alkene group may be substituted or unsubstituted.Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio,arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino,aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl,carboxyalkyl, and carboxyl groups.

By “C₂₋₁₀ alkyne” is meant a branched or unbranched hydrocarbon groupcontaining one or more triple bonds, desirably having from 2 to 10carbon atoms. A C₂₋₁₀ alkyne may optionally include monocyclic,bicyclic, or tricyclic rings, in which each ring desirably has five orsix members. The C₂₋₁₀ alkyne group may be substituted or unsubstituted.Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio,arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino,aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl,carboxyalkyl, and carboxyl groups.

By “C₅₋₁₀ aryl” or “aryl” is meant an aromatic group having a ringsystem with conjugated π electrons (e.g., phenyl, or imidazole). Thering of the aryl group is preferably 5 to 10 atoms. The aromatic ringmay be exclusively composed of carbon atoms or may be composed of amixture of carbon atoms and heteroatoms. Preferred heteroatoms includenitrogen, oxygen, sulfur, and phosphorous. Aryl groups may optionallyinclude monocyclic, bicyclic, or tricyclic rings, where each ring haspreferably five or six members. The aryl group may be substituted orunsubstituted. Exemplary substituents include alkyl, hydroxyl, alkoxy,aryloxy, sulfhydryl, alkylthio, arylthio, halogen, fluoroalkyl,carboxyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino,disubstituted amino, and quaternary amino groups.

As used herein, “C” refers to a chain terminating group. Exemplary chainterminating groups include monofunctional groups containing an amine,alcohol, or carboxylic acid functionality.

As used herein, “complexed” or “complexation” refers to an interaction,either non-covalent or via coordination to a metal center, between acomplexing moiety in an oligofluorinated oligomer (e.g., a branched orlinear oligofluorinated oligomer) or branched compound including waterinsoluble segments contained within a self assembling coating of theinvention and a biologically active agent. Examples of non-covalentbonding interactions which can be used in accordance with the presentinvention include, without limitation, hydrogen bonding, ionicinteractions (e.g., dipole-dipole interactions, ion pairing, and saltformation), inclusion complexes, clathration, van der Waals interactions(e.g., pi-pi stacking), and combinations thereof. The interaction canalso be via coordination to a metal center by both the complexing moietyand the biologically active agent. In some instances, the biologicallyactive agent includes a metal center which is coordinated to thecomplexing moiety.

As used herein, “complexing moiety’ refers to certain embodiments of theinvention including a portion of an oligofluorinated oligomer (e.g., abranched or linear oligofluorinated oligomer) or branched compoundincluding water insoluble segments contained within a self assemblingcoating of the invention which complexes a biologically active agenteither via a non-covalent interaction or coordination to a metal center,forming a polymer complex. The complexing moiety can be a chargedmoiety, e.g., a moiety which loses a proton at physiological pH therebybecoming negatively charged (e.g., carboxylate, or phosphodiester), amoiety which gains a proton at physiological pH thereby becomingpositively charged (e.g., ammonium, guanidinium, or amidinium), a moietythat includes a net formal positive charge without protonation (e.g.,quaternary ammonium), or a moiety that includes a net formal negativecharge without loss of a proton (e.g., borate, BR₄ ⁻). Exemplary chargedcomplexing moieties include, without limitation, carboxylate,phosphodiester, phosphoramidate, borate, phosphate, phosphonate,phosphonate ester, sulfonate, sulfate, thiolate, phenolate, ammonium,amidinium, guanidinium, quaternary ammonium, and imidazoliumfunctionalities. The complexing moiety can be designed to physicallyencapsulate, in whole or in part, the biologically active agent, such asa cyclodextrin. The complexing moiety can be designed to ligate acomplementary oligonucleotide and/or peptide sequence present in thebiologically active agent. The complexing moiety can be designed tocoordinate a metal center including the biologically active agent,either as a ligand alone or including the metal center. A description ofhow make complexing moieties and complexation with biologically activeagents is described in U.S. Patent Publication No. 20070037891,incorporated herein by reference.

As used herein, “covalently tethered” refers to moieties separated byone or more covalent bonds. For example, where an oligofluoro group iscovalently tethered to an oligomer to form an oligofluorinated oligomer,tethered includes the moieties separated by a single bond as well asboth moieties separated by, for example, a LinkB segment to which bothmoieties are covalently attached.

The term “cyclic system” refers to a compound that contains one or morecovalently closed ring structures, in which the atoms forming thebackbone of the ring are composed of any combination of the following:carbon, oxygen, nitrogen, sulfur, and phosphorous. The cyclic system maybe substituted or unsubstituted. Exemplary substituents include, withoutlimitation, alkyl, hydroxyl, alkoxy, aryloxy, sulfhydryl, alkylthio,arylthio, halogen, fluoroalkyl, carboxyl, carboxyalkyl, amino,aminoalkyl, monosubstituted amino, disubstituted amino, and quaternaryamino groups.

As used herein, “dissociation constant in phosphate buffered saline”refers to the equilibrium distribution of biologically active agentbetween a coating of the invention and phosphate buffered saline (137 mMNaCl, 2.7 mM KCl, 10 mM sodium phosphate dibasic, 2 mM potassiumphosphate monobasic and a pH of 7.4) at 25° C. The dissociation constantin phosphate buffered saline is expressed as the percentage ofbiologically active agent present in the phosphate buffered salinesolution at equilibrium and is measured by placing a coating of theinvention in phosphate buffered saline and determining the equilibriumamount of biologically active agent present in the aqueous solution.

As used herein, “excretable” refers to the diffusion of oligofluorinatedoligomer (e.g., a branched or linear oligofluorinated oligomer) orbranched compound including water insoluble segments from the surface ofa transient medical device or tissue surface coated with a selfassembling coating of the invention. Excretable coatings are those inwhich, when dissociated from the self-assembling coatings of theinvention yield only relatively small monomers capable of renal orhepatobiliary excretion without hydrolytic degradation of theoligofluorinated oligomer (e.g., a branched or linear oligofluorinatedoligomer) or branched compound including water insoluble segments.

By “heteroalkyl” is meant a branched or unbranched alkyl group in whichone or more methylenes (—CH₂—) are replaced by nitrogen, oxygen, sulfur,carbonyl, thiocarbonyl, phosphoryl, or sulfonyl moieties. Some examplesinclude tertiary amines, ethers, thioethers, amides, thioamides,carbamates, thiocarbamates, phosphoramidates, sulfonamides, anddisulfides. A heteroalkyl may optionally include monocyclic, bicyclic,or tricyclic rings, in which each ring desirably has three to sixmembers. The heteroalkyl group may be substituted or unsubstituted.Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio,arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino,aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl,carboxyalkyl, and carboxyl groups

As used herein, “LinkB” refers to a coupling segment capable ofcovalently linking or complexing oligomers, biologically active agents,and/or oligofluoro groups. Typically, LinkB molecules have molecularweights ranging from 40 to 700. Preferably the LinkB molecules areselected from the group of functionalized diamines, diisocyanates,disulfonic acids, dicarboxylic acids, diacid chlorides and dialdehydes,wherein the functionalized component has secondary functional chemistrythat is accessed for chemical attachment of an oligofluoro group. Suchsecondary groups include, for example, esters, carboxylic acid salts,sulfonic acid salts, phosphonic acid salts, thiols, vinyls and secondaryamines. Terminal hydroxyls, amines or carboxylic acids on the oligointermediates can react with diamines to form oligo-amides; react withdiisocyanates to form oligo-urethanes, oligo-ureas, oligo-amides; reactwith disulfonic acids to form oligo-sulfonates, oligo-sulfonamides;react with dicarboxylic acids to form oligo-esters, oligo-amides; reactwith diacid chlorides to form oligo-esters, oligo-amides; and react withdialdehydes to form oligo-acetal, oligo-imines.

As used herein, “inhibiting restenosis” refers to reducing there-narrowing of arteries following treatment to clear the blockage, suchas angioplasty, using a therapy of the invention in comparison to there-narrowing that would occur following treatment to clear the blockagein the absence of any further therapy to address the risk of restenosis.

As used herein, the term “non-halogenated organic segment” refers to anorganic oligomer (e.g., having a molecular weight between 100-3,500 Da)that does not include any halogen groups (i.e., F, Cl, Br, or I). Thenon-halogen organic segment is preferably water soluble (e.g., apolyethylene glycol).

As used herein, the term “oligofluorinated oligomer” refers to anoligomer covalently linked to an oligofluoro group. Oligofluorinatedoligomers include, for example, those of any of formulas I-XIV,described herein.

By “oligo” or “oligomer” is meant a relatively short length of arepeating unit or units, generally less than about 50 monomeric unitsand molecular weights less than 10,000 but preferably <5,000 Daltons.Preferably, oligo is selected from the group consisting of polyurethane,polyurea, polyamides, polyalkylene oxide, polycarbonate, polyester,polylactone, polysilicone, polyethersulfone, polyolefin, polyvinyl,polypeptide, polysaccharide; and ether and amine linked segmentsthereof.

By “resorbable” is meant that a portion of the oligofluorinated oligomer(e.g., a branched or linear oligofluorinated oligomer) or branchedcompound including water insoluble segments is designed to be resorbedupon introduction into a mammalian tissue. For example, the oligomerportion of an oligofluorinated oligomer (e.g., a branched or linearoligofluorinated oligomer) or branched compound including waterinsoluble segments can be selected from resorbable polymers, such aspolyesters (e.g., polylactic acid, polyglycolic acid, and mixturesthereof), which can be broken down and assimilated into the mammaliantissue.

As used herein, the term “trifunctional monomer” refers to a smallmolecule (e.g., having a molecular weight between 50-3500 Da) thatincludes three functional groups that can form covalent bonds to anothercompound (e.g., any of the linkers described herein). Exemplarytrifunctional monomers include triols, tricarboxylic acids and acidderivatives, and triisocyanates. Trifunctional monomers that can be usedin the compositions, methods, and transient medical devices describedherein include glycerol, trimethylolpropane (TMP), trimethylolethane(TME), trimesic acid (TMA), tris(hydroxyethyl)isocyanurate (THEIC),pentaerythritol, pyromellitic acid, 1,3,5-trihydroxybenzene, triaminopyrimidine, or melamine.

As used herein, the term “transient medical device” refers to a devicethat is designed to reside only temporarily within the body or mammaliantissue (e.g., only during the performance of a medical procedure and/ordelivery of a biologically active agent to a target tissue). Thetransient medical device is removed within 30 minutes after thebiologically active agent is delivered to the tissue being treated.

As used herein, the term “water insoluble segment” refers to an organicoligomeric segment (e.g., having a molecular weight between 200-3,500 or100-1,500 Da) that is not miscible in water. Exemplary water insolublesegments include the polyfluoroorganic segments described herein, aswell as polysiloxane or polyolefins and other oligomers describedherein.

Other features and advantages of the invention will be apparent from thefollowing Detailed Description, the Drawings, and the Claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration depicting a fluorinated drug deliverycomposition and angioplasty balloon coating. The fluoro-domain providesa shield limiting solubility (because of its inherent water repellingcharacter) during the delivery of the pharmaceutical complex (covalentand non-covalent) to the diseased tissue. The chemistry ofnon-fluorinated segments can be selected in such manner to yield goodbinding to the balloon surface during the transfer to the diseasedtissue.

FIG. 2 is an illustration depicting the deployment of a coated balloonin an occluded vessel. In the second picture frame, the deliverymolecules have lost their ability to form a continuous film because ofballoon expansion at the diseased tissue site, thereby resulting inseparation of the drug from the oligofluorinated molecules which are nowbeginning to hydrate at the drug binding site. In the third pictureframe, the delivery molecule is no longer observed because it hasdissolved into the blood stream where it can be eliminated via the renalsystem.

FIG. 3 is a photo representation of BSA-incubated Nylon films coatedwith Compound 1 showing less protein adsorption (dark blue deposition)than BSA-incubated Nylon films alone. BSA was stained with CoomassieBrilliant Blue R dye.

DETAILED DESCRIPTION

The methods and compositions of the invention feature a self assemblingcoating or formulation including an oligomeric compound (for example, anoligofluorinated oligomer, e.g., a branched or linear oligofluorinatedoligomer, or branched compound including water insoluble segments),preferably a branched compound, and a biologically active agent. Thebiologically active agent can be incorporated within the coating orformulation in a variety of ways, including via non-covalentcomplexation with an oligofluorinated oligomer bearing a complexingmoiety (e.g., incorporated into LINKB, oligo, or F_(T)), via covalentlinkage to an oligofluorinated oligomer, as a physical inclusion.

The coatings and formulations of the invention are conveniently formedby the self assembly of oligomeric compounds (for example,oligofluorinated oligomers, e.g., branched or linear oligofluorinatedoligomers, or branched compound including water insoluble segments),preferably a branched compound, which include a core oligomer, a waterinsoluble segment (e.g., a fluorinated segment), and, optionally, aco-localization site for a biologically active agent. The coatings andformulations can have good blood compatibility (low blood activating),and can be excretable (easily eliminated from the body and withoutlocalization which can lead to reduce chronic local inflammation). Thecentral core allows the delivery platform to bind to a polymeric ormetallic interventional device. The water insoluble segment (e.g., thefluorinated segment) is critical to minimizing blood activation in aflowing blood environment, for shielding the biologically active agentfrom environmental challenges (e.g., degradation and premature releaseof the agent, either as a result of dissolution prior to reaching thesite of treatment, or loss due to tackiness in devices that fold, unfoldor change shape during delivery) until delivered to the diseased tissuesite, and for self assembly of the oligomeric compound (e.g.,oligofluorinated oligomer), preferably branched, into a self assemblingcoating for containing the biologically active agent. The optionalbiologically active agent binding site allows for compatibility of thedelivery system with a wide variety of different therapeutic agents. Theexcretable feature of the self assembling coating and formulation ispart of a strategy to allow simple dissolution and elimination of thecarrier molecule, rather than retention or release of in-situdegradation products that lead to the pro-inflammatory eventscharacteristic of certain drug eluting stents (see Virmani R, SeminInterv Cardiol 3(3-4):163 (1998); Ross et al., Adv Exp Med Biol 102:135(1978); and Barker S G, Atherosclerosis 105(2):131 (1994)).

Oligofluorinated Oligomers and Branched Compounds Including WaterInsoluble Segments

Oligofluorinated Oligomers and Polyfluoroorganic Groups

Oligofluorinated oligomers include an oligo covalently linked to anoligofluoro group and can be described, without limitation, by any offormulas I-XIV.

The oligofluorinated oligomer can be a polymer described by formula (I):

F_(T)-(oligo)-F_(T)  (I),

wherein F_(T) is a polyfluoroorgano group and oligo is an oligomericsegment.

The oligofluorinated oligomer can be a polymer described by formula(II):

wherein (i) F_(T) is a polyfluoroorgano group covalently attached toLinkB, (ii) C is a chain terminating group, (iii) Oligo is an oligomericsegment, (iv) LinkB is a coupling segment, and (v) a is an integergreater than 0 (e.g., an integer from 1 to 50, 1 to 20, or 1 to 10).

The oligofluorinated oligomer can be a polymer described by formula(III):

F_(T)—[B-(oligo)]_(n)-B—F_(T)  (III),

wherein B includes a urethane; oligo is an oligomeric segment; F_(T) isa polyfluoroorgano group; and n is an integer from 1 to 10.

In formulas (I), (II), and (III), the oligo can be a branched ornon-branched oligomeric segment of form 1 to 50 repeating units, such asan oligomeric segment including polyurethane, polyurea, polyamides(including polypeptides), polyalkylene oxide, polycarbonate, polyester,polylactone, polysilicone, polyethersulfone, polyolefin, polyvinylderivative, polypeptide, polysaccharide, polysiloxane,polydimethylsiloxane, polyethylene-butylene, polyisobutylene,polybutadiene, polypropylene oxide (including neopentylglycol, amongother polypropylene oxide derivatives), polyethylene oxide,polytetramethyleneoxide, or polyethylenebutylene segments. In particularembodiments, the oligo includes polypropylene oxide, polyethylene oxide,or polytetramethyleneoxide.

The oligofluorinated oligomer can be a polymer described by formula(IV):

F_(T)—[B-A]_(n)-B—F_(T)  (IV),

wherein (i) A is a soft segment including hydrogenated polybutadiene,poly(2,2 dimethyl-1-3-propylcarbonate), polybutadiene, poly(diethyleneglycol)adipate, poly(hexamethylene carbonate),poly(ethylene-co-butylene), neopentyl glycol-ortho phthalic anhydridepolyester, diethylene glycol-ortho phthalic anhydride polyester,1,6-hexanediol-ortho phthalic anhydride polyester, or bisphenol Aethoxylate; (ii) B is a hard segment including a urethane; (iii) F_(T)is a polyfluoroorgano group; and (iv) n is an integer from 1 to 10. Forexample, the hard segment can be formed from a diisocyanate selectedfrom 3-isocyanatomethyl, 3,5,5-trimethyl cyclohexylisocyanate;4,4′-methylene bis(cyclohexyl isocyanate); 4,4′-methylene bis(phenyl)isocyanate; toluene-2,4 diisocyanate); m-tetramethylxylene diisocyanate;and hexamethylene diisocyanate; and n can be 1 or 2.

The oligofluorinated oligomer can be a polymer described by formulas (V)or (VI):

wherein (i) A is a soft segment; (ii) B is a hard segment including aisocyanurate trimer or biuret trimer; (iii) B′ is a hard segmentincluding a urethane; (iv) each F_(T) is a polyfluoroorgano group; and(v) n is an integer between 0 to 10. soft segment can have a numberaverage molecular weight (Mn), of 500 to 3,500 Daltons and includehydrogenated polybutadiene (HLBH), poly (2,2dimethyl-1-3-propylcarbonate) (PCN), polybutadiene (LBHP),polytetramethylene oxide (PTMO), diethyleneglycol-orthophthalicanhydridepolyester (PDP), hydrogenated polyisoprene (HHTPI), poly(hexamethylenecarbonate), poly(2-butyl-2-ethyl-1,3-propyl carbonate), orhydroxylterminated polydimethylsiloxanes block copolymer (C22). The hardsegment can be formed by reacting a triisocyanate with a diol includingthe soft segment, wherein the triisocyanate is selected fromhexamethylene diisocyanate (HDI) biuret trimer, isophorone diisocyanate(IPDI) trimer, or hexamethylene diisocyanate (HDI) trimer.

Alternatively, the coatings of the invention include a biologicallyactive agent covalently tethered or complexed to the oligofluorinatedoligomer. Such an oligofluorinated oligomer can be described by formula(VII):

wherein oligo is an oligomeric segment; Bio is a biologically activeagent; F_(T) is an oligofluoro group; each Link B is, independently, anorganic moiety covalently bound to oligo, F_(T), or Bio; a is an integergreater than 0 (e.g., 1-50, 1-20, 1-10, or 1-5); b and c are each,independently, integers greater than or equal to 0 (e.g., 1-20, 1-10,1-5, 2-20, 2-10, or 2-5); and d is 0 or 1. The oligomer can include apolyurethane, polyurea, polyamides, polyalkylene oxide, polycarbonate,polyester, polylactone, polysilicone, polyethersulfone, polyolefin,polyvinyl, polypeptide, polysaccharide, or combinations thereof.

In certain coatings, the self assembling coating is formed fromoligofluorinated oligomers including a non-terminal polyfluoroorganogroup, such as those of formula (VIII):

C-(LinkB)-[F_(T)-(LinkB)]_(a)-C  (VIII),

wherein (i) F_(T) is a difunctional polyfluoroorgano group covalentlyattached at both ends to LinkB; (ii) C is a chain terminating group;(iii) LinkB is a coupling segment; and (iv) a is an integer greater than0 (e.g., 1-50, 1-20, 1-20, 1-5, 2-20, 2-10, or 3-20).

The self assembling coating can be formed from a grafted polymerdescribed by formula (IX):

wherein [OLIGO] is an oligomeric polymeric segment; [LINKA] is a firstcoupling segment linking at least two [OLIGO] groups to form(([OLIGO]-[LINKA])_(a))-[OLIGO])) having a theoretical molecular weightof less than 15,000 Da; T is a terminal group; F_(T) is apolyfluoroorgano group; [MRF] is a polyolefin; [INI] is a functionalgroup having the capacity to initiate ATRP, atom transfer radicaladdition (ATRA), or atom transfer radical cyclization (ATRC); [LINKB] isa second coupling segment linking (([OLIGO]-[LINKA])_(a))-[OLIGO])) toF_(T), to T, and/or to [LINKC]; [LINKC] is a third coupling segmentlinking [LINKB] to [INI] or, in the absence of [INI], [LINKC] is adendron of n generations; [Active Agent] is one or more biologicallyactive agents either complexed or covalently tethered to [LINKC] or to[MRF]; each of a and d are, independently, integers greater than 0(e.g., 1-20, 1-10, or 1-5), n is an integer from 1 to 150 (e.g., 1-50,1-20, 1-10, or 1-5); p is an integer from 1 to 20 (e.g., 1-10, 1-5, or2-10); and each of m, p, y, and w are, independently, 0 or an integerfrom 1 to 20 (e.g., 1-10, 1-5, or 2-10); with the provisos that m≦n,w≦y, when m, p, y, and w are 0, then n is an integer from 2 to 150, whenz≧1, then m=0, and when m≧1, then z=0. The portion(([OLIGO]-[LINKA])_(a))-[OLIGO])) can include a polycondensate selectedfrom polyurethane, polyurea, polyamides, polyaklylene oxide,polycarbonate, polyester, polylactone, polysilicone, polyethersulfone,polypeptide, polysaccharide, polysiloxane, polydimethylsiloxane,polypropylene oxide, polyethylene oxide, polytetramethyleneoxide, andcombinations thereof. The portion [MRF] can be selected from polyacrylicacid, polymethacrylic acid, poly(hydroxyethylmethacrylate),poly(hydroxyethylacrylate), poly(methylalkylsulfoxide methacrylate),poly(methylalkylsulfoxide acrylate), polyacrylamide,poly(methacrylamide), poly(dimethylacrylamide),poly(N-isopropyl-acrylamide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(N-vinyl caprolactam), and copolymers thereof. Theportion oligo or oligomer can include, without limitation,polyurethanes, polyureas, polyamides, polyaklylene oxides,polycarbonates, polyesters, polylactones, polysilicones,polyethersulfones, polyolefins, polyvinyl derivatives, polypeptides,polysaccharides, polysiloxanes, polydimethylsiloxanes,polyethylene-butylene, polyisobutylenes, polybutadienes, polypropyleneoxides, polyethylene oxides, polytetramethyleneoxides,polyethylenebutylenes, polycaprolactone, polylactic, polyethyleneglycol, polypropylene glycol, polydiethyleneglycol phthalate,polydiethyleneglycol adipate, polyhydroxybutyrate, polyhydroxyoctanoate,polyhydroxyvalerate, biOII™ soybean oil-derivative (Cargill), andcombinations and mixtures thereof.

The self assembling coating can be a polymerized coating formed from amonomer including (i) two or more cross-linking domains, and (ii) anoligomeric segment having a first end covalently tethered to a firstcross-linking domain and a second end covalently tethered to a secondcross-linking domain, wherein at least one of the cross-linking domainsis an oligofluorinated cross-linking domain. The monomer can further bedescribed by formula (I):

(D)-[(oligo)-(D)]_(n)  (X),

in which oligo is an oligomeric segment; each D is a cross-linkingdomain; and n is an integer from 1 to 20, 1 to 15, 1 to 10, 1 to 8, or 1to 5, and wherein at least one D is an oligofluorinated cross-linkingdomain. Alternatively, the monomer can further be described by formula(XI):

(D)-[(oligo)-(LinkA-F_(T))]_(m)-[(oligo)-(D)]_(n)  (XI),

in which oligo is an oligomeric segment; each D is a cross-linkingdomain; F_(T) is an oligofluoro group; each LinkA-F_(T) is an organicmoiety covalently bound to a first oligo, a second oligo, and F_(T); nis an integer from 1 to 20 (e.g., 1-10, 1-5, or 2-10); and m is aninteger from 1 to 20 (e.g., 1-10, 1-5, or 2-10), wherein at least one Dis an oligofluorinated cross-linking domain. Cross-linking domains whichcan be utilized in the preparation of coatings of the invention includea reactive moiety that capable of chain growth polymerization, such as,without limitation, vinyls, epoxides, aziridines, and oxazolines. Forexample, the cross-linking domain is selected from

The monomer can further be described by formula (XII):

(oligo)_(n)(vinyl)_(m)(F_(T))_(o)  (XII),

in which oligo is an oligomeric segment; vinyl is a cross-linking domainincluding an unsaturated moiety capable of undergoing radical initiatedpolymerization; F_(T) is an oligofluoro group covalently tethered to thevinyl and/or the oligo; and each of n, m, and o is, independently, aninteger from 1 to 5, wherein the monomer includes at least oneoligofluorinated cross-linking domain. The monomer may further bedescribed by formula (XIII):

in which oligo is an oligomeric segment; vinyl is a cross-linking domainincluding an unsaturated moiety capable of undergoing radical initiatedpolymerization; F_(T) is an oligofluoro group; each LinkA is,independently, an organic moiety covalently bound to oligo, F_(T), andvinyl; and each of a, b, and c are, independently, integers greater than0 (e.g., 1-20, 1-10, 1-5, 2-10, or 2-5). The polymerized coating can beprepared by mixing the monomer bearing cross linking domains with anonfluorinated vinyl compound, such as acrylic acid, methyl acrylate,ethyl acrylate, n-butyl acrylate, 2-hydroxyethyl acrylate, n-butylacrylate, glycidyl acrylate, vinyl acrylate, allyl acrylate,2-hydroxyethyl acrylate, 2-hydroxy ethyl methacrylate (HEMA), 2-aminoethyl methacrylate, glycerol monomethacrylate, acrylamide,methacrylamide, N-(3-aminopropyl) methacrylamide, crotonamide, allylalcohol, or 1,1,1-trimethylpropane monoallyl ether.

The self assembling coating can be a polymerized coating formed from amonomer including (i) a first component having a core substituted with mnucleophilic groups, where m≧2; and a second component having a coresubstituted with n electrophilic groups, where n≧2 and m+n>4; whereinthe composition includes at least one oligofluorinated nucleophilicgroup or one oligofluorinated electrophilic group, and wherein the firstcomponent and the second component react to form oligofluorinatedcross-linked polymer. The monomer may further be described by formula(XIV):

in which oligo is an oligomeric segment; G is either a nucleophilicgroup or an electrophilic group; F_(T) is an oligofluoro group; eachLinkA is, independently, an organic moiety covalently bound to oligo,F_(T), and G; and each of a, b, and c are, independently, integersgreater than 0 (e.g., 1-20, 1-10, 1-5, 2-10, or 2-5). To form thepolymerized coating the nucleophilic groups and the electrophilic groupsundergo a nucleophilic substitution reaction, a nucleophilic additionreaction, or both upon mixing. The nucleophilic groups can be selectedfrom, without limitation, primary amines, secondary amines, thiols,alcohols, and phenols. The electrophilic groups can be selected from,without limitation, carboxylic acid esters, acid chloride groups,anhydrides, isocyanato, thioisocyanato, epoxides, activated hydroxylgroups, succinimidyl ester, sulfosuccinimidyl ester, maleimido, andethenesulfonyl. Desirably, the number of nucleophilic groups in themixture is approximately equal to the number of electrophilic groups inthe mixture (i.e., the ratio of moles of nucleophilic groups to moles ofelectrophilic groups is about 2:1 to 1:2, or even about 1:1).

In any of the above formulas the oligofluoro group, F_(T), can be apolyfluoroalkyl having a molecular weight of between 100-1,500 Da. Forexample, F_(T) can be selected from the group consisting of radicals ofthe general formula CF₃(CF₂)_(r)CH₂CH₂— wherein r is 2-20, andCF₃(CF₂)_(s)(CH₂CH₂O)_(χ) wherein χ is 1-10 and s is 1-20; or F_(T) canbe selected from the group consisting of radicals of the general formulaCH_(m)F_((3-m))(CF₂)_(r)CH₂CH₂— andCH_(m)F_((3-m))(CF₂)_(s)(CH₂CH₂O)_(χ)—, wherein m is 0, 1, 2, or 3; χ isan integer between 1-10; r is an integer between 2-20; and s is aninteger between 1-20. In any of the above formulas, F_(T) can beselected from (CF₃)(CF₂)₅CH₂CH₂O—, (CF₃)(CF₂)₇CH₂CH₂O—,(CF₃)(CF₂)₅CH₂CH₂O—, CHF₂(CF₂)₃CH₂O—, and (CF₃)(CF₂)₂CH₂O—,1H,1H,2H,2H-perfluoro-1-decanol; 1H,1H,2H,2H-perfluoro-1-octanol;1H,1H,5H-perfluoro-1-pentanol; and 1H,1H, perfluoro-1-butanol, andmixtures thereof.

The amount of biologically active agent loaded into the coating willdepend upon the design of the oligomer in combination with the desiredrelease profile. The oligomer may be designed for the particular agentbeing delivered and to provide the biocompatibility necessary for aparticular application.

In general, oligofluorinated oligomers used in the methods andcompositions of the invention, and those described by formulas I-XIV canbe prepared as described in U.S. Pat. Nos. 6,127,507, and 6,770,725; PCTPublication Nos. WO20007/004067, WO2007/148230, WO2008/076345, andWO2009/043174; and PCT Application No. PCT/US2009/55418, filed on Aug.28, 2009, each of which is incorporated herein by reference.

Branched Compounds Including Water Insoluble Segments

Branched compounds including water insoluble segments include compoundsdescribed by any of formulas (XV), (XV-A), (XV-B), (XV-C), and (XVII).

The branched compound can be a compound of formula (XV):

wherein m and n are both 0, or m and n are both 1; each A and A₂ is atrifunctional monomer having a molecular weight between 50-300 Da; eachL and L_(A) is, independently, a linker; each R_(X1A), R_(X1B), R_(X2A),and R_(X2B) is, independently, a water insoluble segment having amolecular weight between 100-1,500 Da; and R_(Y1) is a non-halogenatedorganic segment having a molecular weight between 100-1,500 Da; and whenm and n are both 1, each of R_(Z1) and R_(Z2) is, independently, adifunctional water insoluble segment having a molecular weight between50-800 Da, or when m and n are both 0, each of R_(Z1) and R_(Z2) is,independently a water insoluble segment having a molecular weightbetween 100-1,500 Da.

The branched compound can be a compound of formula (XV-A):

wherein A is a trifunctional monomer having a molecular weight between50-300 Da; each L is, independently, a linker; R_(Z1) and R_(Z2) areeach, independently, an organohalide segment having a molecular weightbetween 100-1,500 Da; and R_(Y1) is a non-halogenated organic segmenthaving a molecular weight between 100-1,500 Da. In some embodiments,R_(Z1) and R_(Z2) are fluorinated diols.

The branched compound can be a compound of formula (XV-B):

wherein each of A, A₂, L, L_(A), R_(X1A), R_(X1B), R_(X2A), R_(X2B),R_(Y1), R_(Z1), and R_(Z2) are defined as described in Formula (XV).

For example, in any of formulas (XV), (XV-A), or (XV-B), A can bederived from a triol, or a trifunctional moiety selected from, e.g.,glycerol, trimethylolpropane (TMP), trimethylolethane (TME), trimesicacid (TMA), or tris(hydroxyethyl)isocyanurate (THEIC). In certainembodiments, R_(Y1) is a linear or branched polyethylene glycol, azwitterions (including zwitterionic surfactant moieties, e.g., alkylbetaines, such as alkyl amidopropyl betaine, sulfobetaines and alkylsultaines, alkyl ether hydroxyl propyl sultaines, andalkylamidopropylhydroxy sultaines), or polyvinylpyrrolidone. In otherembodiments, R_(Z1) and R_(Z2) are each, independently, apolyfluoroorgano group, or wherein each of R_(X1A), R_(X1B), R_(X2A),R_(X2B) are each, independently, a polyfluoroorgano group. In stillother embodiments, R_(Z1) and R_(Z2) are each, independently, a siliconegroup, or wherein each of R_(X1A), R_(X1B), R_(X2A), R_(X2B) are each,independently, a silicone group.

The branched compound including water insoluble segments can be acompound of formula (XV-C):

wherein F_(T) is a polyfluoroorgano group; L is a linker; X₁ is H, CH₃,or CH₂CH₃;X₂ is H, CH₃, or CH₂CH₃; and n is an integer from 5 to 50.

The linker of the branched compound including water insoluble segmentscan be described by formula (XVI):

G¹-(Z¹)_(o)—(Y¹)_(u)—(Z²)_(s)—(R₁₀)—(Z³)_(t)—(Y²)_(v)—(Z⁴)_(p)-G²  (XVI)

wherein G¹ is a bond between said polyfluoroorgano group and saidlinker; G² is a bond between said linker and an oxygen atom; Z¹, Z², Z³,and Z⁴ each, independently, is selected from O, S, and NR₁₁; R₁₁ ishydrogen or a C₁₋₁₀ alkyl group; Y¹ and Y² are each, independently,selected from carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; o, p, s,t, u, and v are each, independently, 0 or 1; and R₁₀ is a substituted orunsubstituted C₁₋₁₀ alkyl, a heteroalkyl of 1 to 10 atoms, a C₂₋₁₀alkene, a C₂₋₁₀ alkyne, a C₅₋₁₀ aryl, a cyclic system of 3 to 10 atoms,—(CH₂CH₂O)_(q)CH₂CH₂— in which q is an integer of 1 to 10, or a chemicalbond linking G¹-(Z¹)_(o)—(Y¹)_(u)—(Z²)_(s)— to—(Z³)_(t)—(Y²)_(v)—(Z⁴)_(p)-G². In certain embodiments, the linker is acovalent bond or a —(C═O)— group.

The branched compound including water insoluble segments can be acompound of formula (XVII):

wherein F_(T) is a polyfluoroorgano group; L₂ is a substituted orunsubstituted C₁₋₁₀ alkyl, a heteroalkyl of 1 to 10 atoms, a C₂₋₁₀alkene, a C₂₋₁₀ alkyne, a C₅₋₁₀ aryl, a cyclic system of 3 to 10 atoms,—(CH₂CH₂O)_(q)CH₂CH₂— in which q is an integer of 1 to 10; X₁ is H, CH₃,or CH₂CH₃; X₂ is H, CH₃, or CH₂CH₃; and n is an integer from 5 to 50. Incertain embodiments, the polyfluoroorgano group is a polyfluoroalkylhaving a molecular weight of between 100-1,500 Da. In other embodiments,the polyfluoroorgano group is a radical of the general formulaCF₃(CF₂)_(r)CH₂CH₂— or CF₃(CF₂)_(s)(CH₂CH₂O)_(χ)—, wherein r is aninteger from 2-20, χ is an integer from 1-10, and s is an integer from1-20. In still other embodiments, the polyfluoroorgano group is aradical of the general formula CH_(m)F_((3-m))(CF₂)_(r)CH₂CH₂— orCH_(m)F_((3-m))(CF₂)_(s)(CH₂CH₂O)_(χ)—, wherein m is 0, 1, 2, or 3; χ isan integer between 1-10; r is an integer between 2-20; and s is aninteger between 1-20. In certain embodiments, the polyfluoroorgano groupis selected from (CF₃)(CF₂)₅CH₂CH₂O—, (CF₃)(CF₂)₇CH₂CH₂O—,(CF₃)(CF₂)₅CH₂CH₂O—, CHF₂(CF₂)₃CH₂O—, and (CF₃)(CF₂)₂CH₂O—,1H,1H,2H,2H-perfluoro-1-decanol; 1H,1H,2H,2H-perfluoro-1-octanol;1H,1H,5H-perfluoro-1-pentanol; and 1H,1H, perfluoro-1-butanol, andmixtures thereof.

Water Insoluble Segments

The branched compounds described herein (e.g., compositions of Formulas(XV), (XV-A), (XV-B), (XV-C), and (XVII)) include water insolublesegments. Exemplary water insoluble segments include polyfluoroorganogroups (e.g., the F_(T) groups described herein), polysulfones, aromaticpolyimides, and amides. Others include polysiloxanes, polyolefins suchas C10, C12 and other saturated or unsaturated hydrocarbons.

Linkers

The branched compound including water insoluble segments describedherein (e.g., compositions of Formulas (XV), (XV-A), (XV-B), (XV-C), and(XVII)) include linkers. The linker component of the invention is, atits simplest, a bond between the trifunctional monomer and theorganohalide segment (e.g., a polyfluoroorgano group) or thenon-halogenated organic segment. The linker can be a linear, cyclic, orbranched molecular skeleton, optionally having pendant groups.

Thus, the linking of the trifunctional monomer and the organohalidesegment (e.g., a polyfluoroorgano group) or the non-halogenated organicsegment is achieved by covalent means, involving bond formation with oneor more functional groups located on each group. Examples of chemicallyreactive functional groups which may be employed for this purposeinclude, without limitation, amino, hydroxyl, sulfhydryl, carboxyl,carbonyl, carbohydrate groups, vicinal diols, thioethers,2-aminoalcohols, 2-aminothiols, guanidinyl, imidazolyl, and phenolicgroups.

The covalent linking of the trifunctional monomer and the organohalidesegment (e.g., a polyfluoroorgano group) or the non-halogenated organicsegment may be effected using a linker which contains reactive moietiescapable of reaction with such functional groups present in thetrifunctional monomer and the organohalide segment or thenon-halogenated organic segment. For example, a hydroxyl group of thetrifunctional monomer may react with a carboxyl group of the linker, oran activated derivative thereof, resulting in the formation of an esterlinking the two.

Examples of moieties capable of reaction with sulfhydryl groups includeα-haloacetyl compounds of the type XCH₂CO— (where X=Br, Cl or I), whichshow particular reactivity for sulfhydryl groups, but which can also beused to modify imidazolyl, thioether, phenol, and amino groups asdescribed by Gurd, Methods Enzymol. 11:532 (1967). N-Maleimidederivatives are also considered selective towards sulfhydryl groups, butmay additionally be useful in coupling to amino groups under certainconditions. Reagents such as 2-iminothiolane (Traut et al., Biochemistry12:3266 (1973)), which introduce a thiol group through conversion of anamino group, may be considered as sulfhydryl reagents if linking occursthrough the formation of disulphide bridges.

Examples of reactive moieties capable of reaction with amino groupsinclude, for example, alkylating and acylating agents. Representativealkylating agents include:

(i) α-haloacetyl compounds, which show specificity towards amino groupsin the absence of reactive thiol groups and are of the type XCH₂CO—(where X=Cl, Br or I), for example, as described by Wong Biochemistry24:5337 (1979);(ii) N-maleimide derivatives, which may react with amino groups eitherthrough a Michael type reaction or through acylation by addition to thering carbonyl group, for example, as described by Smyth et al., J. Am.Chem. Soc. 82:4600 (1960) and Biochem. J. 91:589 (1964); (iii) arylhalides such as reactive nitrohaloaromatic compounds; (iv) alkylhalides, as described, for example, by McKenzie et al., J. Protein Chem.7:581 (1988); (v) aldehydes and ketones capable of Schiff's baseformation with amino groups, the adducts formed usually being stabilizedthrough reduction to give a stable amine; (vi) epoxide derivatives suchas epichlorohydrin and bisoxiranes, which may react with amino,sulfhydryl, or phenolic hydroxyl groups; (vii) chlorine-containingderivatives of s-triazines, which are very reactive towards nucleophilessuch as amino, sulfhydryl, and hydroxyl groups; (viii) aziridines basedon s-triazine compounds detailed above, e.g., as described by Ross, J.Adv. Cancer Res. 2:1 (1954), which react with nucleophiles such as aminogroups by ring opening; (ix) squaric acid diethyl esters as described byTietze, Chem. Ber. 124:1215 (1991); and (x) α-haloalkyl ethers, whichare more reactive alkylating agents than normal alkyl halides because ofthe activation caused by the ether oxygen atom, as described by Bennecheet al., Eur. J. Med. Chem. 28:463 (1993).

Representative amino-reactive acylating agents include: (i) isocyanatesand isothiocyanates, particularly aromatic derivatives, which formstable urea and thiourea derivatives respectively; (ii) sulfonylchlorides, which have been described by Herzig et al., Biopolymers 2:349(1964); (iii) acid halides; (iv) active esters such as nitrophenylestersor N-hydroxysuccinimidyl esters; (v) acid anhydrides such as mixed,symmetrical, or N-carboxyanhydrides; (vi) other useful reagents foramide bond formation, for example, as described by M. Bodansky,Principles of Peptide Synthesis, Springer-Verlag, 1984; (vii)acylazides, e.g. wherein the azide group is generated from a preformedhydrazide derivative using sodium nitrite, as described by Wetz et al.,Anal. Biochem. 58:347 (1974); and (viii) imidoesters, which form stableamidines on reaction with amino groups, for example, as described byHunter and Ludwig, J. Am. Chem. Soc. 84:3491 (1962). Aldehydes andketones may be reacted with amines to form Schiff's bases, which mayadvantageously be stabilized through reductive amination. Alkoxylaminomoieties readily react with ketones and aldehydes to produce stablealkoxamines, for example, as described by Webb et al., in BioconjugateChem. 1:96 (1990).

Examples of reactive moieties capable of reaction with carboxyl groupsinclude diazo compounds such as diazoacetate esters and diazoacetamides,which react with high specificity to generate ester groups, for example,as described by Herriot, Adv. Protein Chem. 3:169 (1947). Carboxylmodifying reagents such as carbodiimides, which react through O-acylureaformation followed by amide bond formation, may also be employed.

It will be appreciated that functional groups in the trifunctionalmonomer and the organohalide segment or the non-halogenated organicsegment may, if desired, be converted to other functional groups priorto reaction, for example, to confer additional reactivity orselectivity. Examples of methods useful for this purpose includeconversion of amines to carboxyls using reagents such as dicarboxylicanhydrides; conversion of amines to thiols using reagents such asN-acetylhomocysteine thiolactone, S-acetylmercaptosuccinic anhydride,2-iminothiolane, or thiol-containing succinimidyl derivatives;conversion of thiols to carboxyls using reagents such as α-haloacetates;conversion of thiols to amines using reagents such as ethylenimine or2-bromoethylamine; conversion of carboxyls to amines using reagents suchas carbodiimides followed by diamines; and conversion of alcohols tothiols using reagents such as tosyl chloride followed bytransesterification with thioacetate and hydrolysis to the thiol withsodium acetate.

So-called zero-length linkers, involving direct covalent joining of areactive chemical group of the trifunctional monomer and theorganohalide segment or the non-halogenated organic segment withoutintroducing additional linking material may, if desired, be used inaccordance with the invention. Most commonly, however, the linker willinclude two or more reactive moieties, as described above, connected bya spacer element. The presence of such a spacer permits bifunctionallinkers to react with specific functional groups within thecorticosteroid and the bulky or charged group, resulting in a covalentlinkage between the two. The reactive moieties in a linker may be thesame (homobifunctional linker) or different (heterobifunctional linker,or, where several dissimilar reactive moieties are present,heteromultifunctional linker), providing a diversity of potentialreagents that may bring about covalent attachment between thetrifunctional monomer and the non-halogenated organic segment or waterinsoluble segment.

Spacer elements in the linker typically consist of linear or branchedchains and may include a C₁₋₁₀ alkyl, a heteroalkyl of 1 to 10 atoms, aC₂₋₁₀ alkene, a C₂₋₁₀ alkyne, C₅₋₁₀ aryl, a cyclic system of 3 to 10atoms, or —(CH₂CH₂O)_(n)CH₂CH₂—, in which n is 1 to 4.

Biologically Active Agents

The coatings of the invention include one or more biologically activeagents. The incorporation can be achieved by mixing the self assemblingcoating components (for example, an oligofluorinated oligomer (e.g., abranched or linear oligofluorinated oligomer) or a branched compoundincluding water insoluble segments) and the biologically active agenttogether and applying the mixture to the surface of the article prior toimplantation. In some instances, the biologically active agent iscovalently tethered or complexed to an oligomeric compound (for example,an oligofluorinated oligomer (e.g., a branched or linearoligofluorinated oligomer) or a branched compound including waterinsoluble segments), preferably a branched compound, in the selfassembling coating. A detailed description of how biologically activeagents may be covalently tethered or complexed to an oligofluorinatedoligomer is provided in U.S. Pat. No. 6,770,725 and U.S. PatentPublication No. 20070037891, each of which is incorporated herein byreference. Biologically active agents that can be used in the methodsand compositions of the invention include therapeutic, diagnostic, andprophylactic agents. They can be naturally occurring compounds,synthetic organic compounds, or inorganic compounds. Biologically activeagents that can be used in the methods and compositions of the inventioninclude, but are not limited to, proteins, peptides, carbohydrates,antibiotics, antiproliferative agents, rapamycin macrolides, analgesics,anesthetics, antiangiogenic agents, vasoactive agents, anticoagulants,immunomodulators, cytotoxic agents, antiviral agents, antithromboticdrugs, such as terbrogrel and ramatroban, antibodies, neurotransmitters,psychoactive drugs, oligonucleotides, proteins, lipids, and anybiologically active agent described herein.

Exemplary therapeutic agents include growth hormone, for example humangrowth hormone, calcitonin, granulocyte macrophage colony stimulatingfactor (GMCSF), ciliary neurotrophic factor, and parathyroid hormone.Other specific therapeutic agents include parathyroid hormone-relatedpeptide, somatostatin, testosterone, progesterone, estradiol, nicotine,fentanyl, norethisterone, clonidine, scopolomine, salicylate,salmeterol, formeterol, albeterol, valium, heparin, dermatan,ferrochrome A, erythropoetins, diethylstilbestrol, lupron, estrogenestradiol, androgen halotestin, 6-thioguanine, 6-mercaptopurine,zolodex, taxol, lisinopril/zestril, streptokinase, aminobutytric acid,hemostatic aminocaproic acid, parlodel, tacrine, potaba, adipex,memboral, phenobarbital, insulin, gamma globulin, azathioprine, papein,acetaminophen, ibuprofen, acetylsalicylic acid, epinephrine,flucloronide, oxycodone percoset, dalgan, phreniline butabital,procaine, novocain, morphine, oxycodone, aloxiprin, brofenac,ketoprofen, ketorolac, hemin, vitamin B-12, folic acid, magnesium salts,vitamine D, vitamin C, vitamin E, vitamin A, Vitamin U, vitamin L,vitamin K, pantothenic acid, aminophenylbutyric acid, penicillin,acyclovir, oflaxacin, amoxicillin, tobramycin, retrovior, epivir,nevirapine, gentamycin, duracef, ablecet, butoxycaine, benoxinate,tropenzile, diponium salts, butaverine, apoatropine, feclemine,leiopyrrole, octamylamine, oxybutynin, albuterol, metaproterenol,beclomethasone dipropionate, triamcinolone acetamide, budesonideacetonide, ipratropium bromide, flunisolide, cromolyn sodium, ergotaminetartrate, and protein or peptide drugs such as TNF antagonists orinterleukin antagonists. For example, the biologically active agent canbe an antiinflammatory agent, such as an NSAID, corticosteriod, or COX-2inhibitor, e.g., rofecoxib, celecoxib, valdecoxib, or lumiracoxib.

Exemplary diagnostic agents include imaging agents, such as those thatare used in positron emission tomography (PET), computer assistedtomography (CAT), single photon emission computerized tomography, X-ray,fluoroscopy, and magnetic resonance imaging (MRI). Suitable materialsfor use as contrast agents in MRI include gadolinium chelates, as wellas iron, magnesium, manganese, copper, and chromium chelates. Examplesof materials useful for CAT and X-rays include iodine based materials.

A preferred biologically active agent is a substantially purifiedpeptide or protein. Proteins are generally defined as consisting of 100amino acid residues or more; peptides are less than 100 amino acidresidues. Unless otherwise stated, the term protein, as used herein,refers to both proteins and peptides. The proteins may be produced, forexample, by isolation from natural sources, recombinantly, or throughpeptide synthesis. Examples include growth hormones, such as humangrowth hormone and bovine growth hormone; enzymes, such as DNase,proteases, urate oxidase, alronidase, alpha galactosidase, and alphaglucosidase; antibodies, such as trastuzumab.

Rapamycin Macrolides

Rapamycin (Sirolimus) is an immunosuppressive lactam macrolide that isproduced by Streptomyces hygroscopicus. See, for example, McAlpine, J.B., et al., J. Antibiotics 44: 688 (1991); Schreiber, S. L., et al., J.Am. Chem. Soc. 113: 7433 (1991); and U.S. Pat. No. 3,929,992,incorporated herein by reference. Exemplary rapamycin macrolides whichcan be used in the methods and compositions of the invention include,without limitation, rapamycin, CCI-779, Everolimus (also known asRAD001), and ABT-578. CCI-779 is an ester of rapamycin (42-ester with3-hydroxy-2-hydroxymethyl-2-methylpropionic acid), disclosed in U.S.Pat. No. 5,362,718. Everolimus is an alkylated rapamycin(40-O-(2-hydroxyethyl)-rapamycin, disclosed in U.S. Pat. No. 5,665,772.

Antiproliferative Agents

Exemplary antiproliferative agents which can be used in the methods andcompositions of the invention include, without limitation,mechlorethamine, cyclophosphamide, iosfamide, melphalan, chlorambucil,uracil mustard, estramustine, mitomycin C, AZQ, thiotepa, busulfan,hepsulfam, carmustine, lomustine, semustine, streptozocin, dacarbazine,cisplatin, carboplatin, procarbazine, methotrexate, trimetrexate,fluouracil, floxuridine, cytarabine, fludarabine, capecitabine,azacitidine, thioguanine, mercaptopurine, allopurine, cladribine,gemcitabine, pentostatin, vinblastine, vincristine, etoposide,teniposide, topotecan, irinotecan, camptothecin, 9-aminocamptothecin,paclitaxel, docetaxel, daunorubicin, doxorubicin, dactinomycin,idarubincin, plicamycin, mitomycin, amsacrine, bleomycin,aminoglutethimide, anastrozole, finasteride, ketoconazole, tamoxifen,flutamide, leuprolide, goserelin, Gleevec™ (Novartis), leflunomide(Pharmacia), SU5416 (Pharmacia), SU6668 (Pharmacia), PTK787 (Novartis),Iressa™ (AstraZeneca), Tarceva™, (Oncogene Science), trastuzumab(Genentech), Erbitux™ (ImClone), PKI166 (Novartis), GW2016(GlaxoSmithKline), EKB-509 (Wyeth), EKB-569 (Wyeth), MDX-H210 (Medarex),2C4 (Genentech), MDX-447 (Medarex), ABX-EGF (Abgenix), CI-1033 (Pfizer),Avastin™ (Genentech), IMC-1C11 (ImClone), ZD4190 (AstraZeneca), ZD6474(AstraZeneca), CEP-701 (Cephalon), CEP-751 (Cephalon), MLN518(Millenium), PKC412 (Novartis), 13-cis-retinoic acid, isotretinoin,retinyl palmitate, 4-(hydroxycarbophenyl) retinamide, misonidazole,nitracrine, mitoxantrone, hydroxyurea, L-asparaginase, interferon alfa,AP23573, Cerivastatin, Troglitazone, CRx-026DHA-paclitaxel, Taxoprexin,TPI-287, Sphingosine-based lipids, and mitotane.

Corticosteroids

Exemplary corticosteroids which can be used in the methods andcompositions of the invention include, without limitation,21-acetoxypregnenolone, alclomerasone, algestone, amcinonide,beclomethasone, betamethasone, betamethasone valerate, budesonide,chloroprednisone, clobetasol, clobetasol propionate, clobetasone,clobetasone butyrate, clocortolone, cloprednol, corticosterone,cortisone, cortivazol, deflazacon, desonide, desoximerasone,dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone,fluazacort, flucloronide, flumethasone, flumethasone pivalate,flunisolide, flucinolone acetonide, fluocinonide, fluorocinoloneacetonide, fluocortin butyl, fluocortolone, fluorocortolone hexanoate,diflucortolone valerate, fluorometholone, fluperolone acetate,fluprednidene acetate, fluprednisolone, flurandenolide, formocortal,halcinonide, halometasone, halopredone acetate, hydrocortamate,hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate,hydrocortisone phosphate, hydrocortisone 21-sodium succinate,hydrocortisone tebutate, mazipredone, medrysone, meprednisone,methylprednicolone, mometasone furoate, paramethasone, prednicarbate,prednisolone, prednisolone 21-diedryaminoacetate, prednisolone sodiumphosphate, prednisolone sodium succinate, prednisolone sodium21-m-sulfobenzoate, prednisolone sodium 21-stearoglycolate, prednisolonetebutate, prednisolone 21-trimethylacetate, prednisone, prednival,prednylidene, prednylidene 21-diethylaminoacetate, tixocortol,triamcinolone, triamcinolone acetonide, triamcinolone benetonide andtriamcinolone hexacetonide. Structurally related corticosteroids havingsimilar anti-inflammatory properties are also intended to be encompassedby this group.

NSAIDs

Exemplary non-steroidal antiinflammatory drugs (NSAIDs) which can beused in the methods and compositions of the invention include, withoutlimitation, naproxen sodium, diclofenac sodium, diclofenac potassium,aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen,nabumetone, choline magnesium trisalicylate, sodium salicylate,salicylsalicylic acid (salsalate), fenoprofen, flurbiprofen, ketoprofen,meclofenamate sodium, meloxicam, oxaprozin, sulindac, and tolmetin.

Analgesics

Exemplary analgesics which can be used in the methods and compositionsof the invention include, without limitation, morphine, codeine, heroin,ethylmorphine, O-carboxymethylmorphine, O-acetylmorphine, hydrocodone,hydromorphone, oxymorphone, oxycodone, dihydrocodeine, thebaine,metopon, ethorphine, acetorphine, diprenorphine, buprenorphine,phenomorphan, levorphanol, ethoheptazine, ketobemidone, dihydroetorphineand dihydroacetorphine.

Antimicrobials

Exemplary antimicrobials which can be used in the methods andcompositions of the invention include, without limitation, penicillin G,penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin,nafcillin, ampicillin, amoxicillin, carbenicillin, ticarcillin,mezlocillin, piperacillin, azlocillin, temocillin, ccpalothin,cephapirin, cephradine, cephaloridine, cefazolin, cefamandole,cefuroxime, cephalexin, cefprozil, cefaclor, loracarbef, cefoxitin,cefmatozole, cefotaxime, ceflizoxime, ceftriaxone, cefoperazone,ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir, cefpirome,cefepime, BAL5788, BAL9141, imipenem, ertapenem, meropenem, astreonam,clavulanate, sulbactam, tazobactam, streptomycin, neomycin, kanamycin,paromycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin,sisomicin, dibekalin, isepamicin, tetracycline, chlortetracycline,demeclocycline, minocycline, oxytetracycline, methacycline, doxycycline,erythromycin, azithromycin, clarithromycin, telithromycin, ABT-773,lincomycin, clindamycin, vancomycin, oritavancin, dalbavancin,teicoplanin, quinupristin and dalfopristin, sulphanilamide,para-aminobenzoic acid, sulfadiazine, sulfisoxazole, sulfamethoxazole,sulfathalidine, linezolid, nalidixic acid, oxolinic acid, norfloxacin,perfloxacin, enoxacin, ofloxacin, ciprofloxacin, temafloxacin,lomefloxacin, fleroxacin, grepafloxacin, sparfloxacin, trovafloxacin,clinafloxacin, gatifloxacin, moxifloxacin, gemifloxacin, sitafloxacin,metronidazole, daptomycin, garenoxacin, ramoplanin, faropenem,polymyxin, tigecycline, AZD2563, and trimethoprim.

Local Anesthetics

Exemplary local anesthetics which can be used in the methods andcompositions of the invention include, without limitation, cocaine,procaine, lidocaine, prilocaine, mepivicaine, bupivicaine, articaine,tetracaine, chloroprocaine, etidocaine, and ropavacaine.

Antispasmodics

Exemplary antispasmodics which can be used in the methods andcompositions of the invention include, without limitation, atropine,belladonna, bentyl, cystospaz, detrol (tolterodine), dicyclomine,ditropan, donnatol, donnazyme, fasudil, flexeril, glycopyrrolate,homatropine, hyoscyamine, levsin, levsinex, librax, malcotran, novartin,oxyphencyclimine, oxybutynin, pamine, tolterodine, tiquizium, prozapine,and pinaverium.

Coatings

The coatings of the invention can be designed to vary in adhesion to asurface by varying the size of oligomers, their solubility inphysiological media, and/or employing oligomers which favorably interactwith the surface on which the coating is placed. Such favorableinteractions can include, for example, coordinatation (i.e., carboxylategroups coordinating to a metal surface), and/or hydrogen bonding betweenthe oligomers and the device surface. In certain embodiments, the selfassembling coating is applied to the surface of the implantable medicaldevice to form a thin coating (i.e., 0.5-50.0 microns in thickness).Because the coatings of the invention do not have the properties of abase polymer, they are not susceptible to flaking or cracking during thephysical manipulation of the device, such as the crimping and deploymentof a stent. The coatings of the invention can control the release ofbiologically active agents incorporated within the self assemblingcoating by limiting the rate of diffusion of the agent from the selfassembling coating prior to disruption of the coating (e.g., bydeformation of the coating, or by exposing the coating to an energysource).

A primary function of such coating can be to increase efficacy of localdelivery of a biologically active agent for a defined period of time.The self assembling coating is optionally complexed, or covalentlytethered, or physically combined with a biologically active agent, orapplied in a mixture including a biologically active agent. The amountof biologically active agent loaded into the self assembling coatingwill depend upon the desired local concentration and release profilefrom the self assembling coating.

In some embodiments, the coatings of the invention contain a waterinsoluble segment (e.g., fluorinated segment) which provides a desiredsurface fluorine factor. The fluorinated moiety, functions as a shieldto biological agent incorporated within the self assembling coating,from undesirable interaction with physiological media (e.g. fluid andblood components). This allows effective dose transfer of the activeagent to the target site with limited transfer of the delivery platform.The biologically active agent can be covalently bound to an oligomericcompound (for example, an oligofluorinated oligomer (e.g., a branched orlinear oligofluorinated oligomer) or a branched compound including waterinsoluble segments), preferably a branched compound, as describedherein, in the self assembling coating via a hydrolyzable linker. Inthese embodiments, it is understood that the hydrolysis of the linkercan occur either within the self assembling coating or after diffusionof the biologically active agent from the surface of the device. It isdesirable to limit hydrolytic degradation near the site of implantationto avoid localized changes in pH and the generation of inflammatory sideproducts.

The coatings of the invention can be applied to the surface of a medicaldevice in any number of ways including, but not limited, toelectrodeposition, dipping, spraying, brushing, printing, or spincoating of the self assembling coating material from a solution orsuspension followed by solvent removal step as needed. Furtherdescription of how the coatings can be made and applied is found in theExamples.

The self assembling coating can be formed by combining the components,one or more oligomeric compounds (for example, an oligofluorinatedoligomer (e.g., a branched or linear oligofluorinated oligomer) or abranched compound including water insoluble segments), preferablybranched compounds, and biologically active agents, in solution, assolid or suspension. The self assembling coating can be applied onto thesurface of medical device followed by solvent removal step as needed.Alternatively, the components of a coating can be applied in a layeredfashion (e.g., an oligofluorinated oligomer (e.g., a branched or linearoligofluorinated oligomer) or a branched compound including waterinsoluble segments can be applied onto the surface of medical device asa base layer, followed by biologically active agents as the top layer(e.g., the biologically active agent(s) can be in combination with abranched oligomeric compound such as an oligofluorinated oligomer), oran oligofluorinated oligomer (e.g., a branched or linearoligofluorinated oligomer) or a branched compound including waterinsoluble segments, preferably a branched oligomeric compound, can beapplied to medical device surface as a top coat, enveloping the baselayer of biologically active agent(s) (e.g., can be in combination withthe oligofluorinated oligomer (e.g., a branched or linearoligofluorinated oligomer) or branched compound including waterinsoluble segments)). Multiple alternating layers can be applied, asneeded. Optionally, the self assembling coatings of the invention caninclude a cofactor binder to improve the binding of the self assemblingcoating to the device surface or the component composition of the selfassembling coating. The coatings can be formed by mixing theoligofluorinated oligomer (e.g., a branched or linear oligofluorinatedoligomer) or branched compound including water insoluble segments,cofactor binder, and biologically active agent(s), and applied to thesurface of medical device. Such coatings can be formed by applying theoligofluorinated oligomer (e.g., a branched or linear oligofluorinatedoligomer) or a branched compound including water insoluble segments asthe base coat, followed by biologically active agents as the top coatwith cofactor binder layer in the middle, or vice versa. Cofactorbinders which can be used in the coatings of the invention include,without limitation, carbowax, gelatin, albumin gel, dextrose, iodinesalt, polysaccharide, lipids, nucleic acid, PEG, sodium citrates,dicalcium phosphate, lactose, sucrose, glucose, mannitol, silicic acid,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,acacia, glycerol, agar-agar, paraffin, pluronic gel, glycerolmonostearate, kaolin, calcium/magnesium stearate, solid polyethyleneglycols, sodium lauryl sulfate, and propylene glycol.

The self assembling coatings of the invention can also be applieddirectly to a tissue surface to be treated. When applied directly, thecomponents of the coating can be mixed and applied onto the surfacebeing treated. With this approach it is desirable to employ anexcretable oligomeric compound (e.g., oligofluorinated oligomer (e.g., abranched or linear oligofluorinated oligomer) or a branched compoundincluding water insoluble segments), preferably a branched compound, inthe self assembling coating.

Coated Medical Devices

A wide variety of implantable medical devices can be coated using thecompositions and methods of the invention to improve theirbiocompatibility and to deliver biologically active agents at a desiredsite of treatment. The medical devices can include transient medicaldevices, non-implantable vascular, non-vascular, percutaneous, andcutanous devices. Percutaneous devices include items that penetrate theskin, thereby extending from outside the body into the body. Cutaneousdevices are used superficially. Percutaneous devices include categoriesthat penetrates the skin, thereby extending from outside the body intothe body, without limitation, catheters of various types, ballooncatheter, neuron guiding catheter, neuron microcatheter, neuronmicrowire, neuron balloon, coronary wires, coronary guiding catheter,stent grafts, stent delivery system, coronary wires, coronary guidingcatheter, introducer sheath, dilator, guidewire, syringe needle,dialysis sheath cannulas, filters, drainage tubes such as chest tubes,surgical instruments such as forceps, retractors, needles, and cathetercuffs.

The transient medical devices of the invention can include energysources including ultrasound, heat, electromagnetic, and/or vibrationalenergy sources for disrupting the self assembling coating and releasingthe biologically active agent. For example, an ultrasound externalenergy source may be used having a frequency in a range from 20 kHz to100 MHz, preferably in a range from 0.1 MHz to 20 MHz, and an intensitylevel in a range from 0.05 W/cm² to 10 W/cm², preferably in a range from0.5 W/cm² to 5 W/cm². The ultrasound energy would be directed at theself assembling coating coating and either continuously applied orpulsed, for a time period in a range from 5 sec to 30 minutes,preferably in a range from 1 minute to 15 minutes. Alternatively, thetemperature of the surface of the transient medical device can be heated(e.g., in the range of from 36° C. to 48° C.), vibrated, or subjected toelectromagnetic energy to facilitate the release of biologically activeagent at the desired place and time.

In another approach, the self assembling coating is disruptedmechanically upon deformation of the surface of the device (e.g.,expansion of the device). For example, the transient medical devices ofthe invention can include a radially expandable segment that can beconverted from a small diameter configuration to a radially expanded,usually cylindrical, configuration which is achieved when the expandablestructure is positioned at a desired target site. The expandablestructure may be minimally resilient, e.g., malleable, thus requiringthe application of an internal force to expand and set it at the targetsite. Typically, the expansive force can be provided by a balloon, oranother self-expanding structure. Expandable transient medical devicesfor use in the present invention can utilize a resilient material, suchas a tempered stainless steel, or a superelastic alloy such as aNitinol™ alloy, and forming the body segment so that it possesses itsdesired, radially-expanded diameter when it is unconstrained, i.e.released from the radially constraining forces of a sheath. Theself-expanding expandable structure can be tracked and delivered in itsradially constrained configuration, e.g., by placing the expandablestructure within a delivery sheath or tube and removing the sheath atthe target site. The dimensions of the expandable structure will dependon its intended site of use. Typically, the expandable structure willhave a length in a range from about 5 mm to about 100 mm, usually beingfrom about 8 mm to about 50 mm, for vascular applications. The diameterof a cylindrically shaped expandable structure for vascularapplications, in a non-expanded configuration, usually ranges from about0.5 mm to about 10 mm, more usually from about 0.8 mm to about 8 mm;with the diameter in an expanded configuration ranging from about 1.0 mmto about 100 mm, preferably from about 2.0 mm to about 30 mm. Theexpandable structure usually will have a thickness in a range from about0.025 mm to 2.0 mm, preferably from about 0.05 mm to about 0.5 mm.

Drug Eluting Balloon (DEB)

Vascular occlusive diseases are mainly caused by changes inpathophysiobiology of the vasculature, resulting in thickening of thevessel lining from fatty deposits or plaques. The most popular mode oftherapy for vascular occlusive diseases is the surgical bypass. However,endovascular interventions have been recognized and practiced as analternative and viable mode of therapy. Balloon angioplasty is designedto expand occluded blood vessels based on balloon inflation, andcompression of plaque, allowing perfusion of the diseased tissue. Inmost endovascular interventions a guiding catheter is advanced in thepatient's vasculature until the distal tip of the guiding catheter islocated close to the targeted location. A guidewire is advanced out ofthe distal end of the guiding catheter into the patient's blood vessel,until the distal end of the guidewire crosses a lesion to be dilated. Adilation catheter having an inflatable balloon on the distal portionthereof is advanced into the patient's blood vessel over previouslyintroduced guidewire until the balloon of the dilatation catheter isproperly positioned across the lesion. The success of the endovascularintervention is generally high, but the vessel patency is often reduceddue to restenosis in the vicinity of the original lesion causingre-occlusion of the vessel. The ability to locally deliverpharmaceuticals from a balloon surface provides an approach incontrolling restenosis. The entire or partial external balloon surfacecan be coated with a desired pharmaceutical, the time of ballooninflation or the multiplicity of inflation can also be controlled,making the “drug eluting balloon” an adaptable and robust tool for localdrug delivery.

The compositions and methods of this invention can be used in variousapplications of drug eluting balloon technology, such as percutaneoustranslumenal angioplasty (PTA), coronary angioplasty (PTCA),neurovascular angioplasty (PTNA), balloon aortic valvuplasty (BAV).Furthermore, the composition of the invention allows incorporation ofvarious biological agents depending on the application of the drugeluting balloons.

In one application, DEB can also be used as balloon aortic valvuplastyto repair stenotic aortic valve which has become stiff from calciumbuildup. The balloon is inserted and inflated into the aortic valve toincrease the opening size of the valve and improving blood flow.Traditional balloon aortic valvuloplasty many times fails to preventrestenosis in patients. Drug eluting balloon in this case allows theincorporated antirestenotic drug to elute into dilated aortic valves toprevent restenosis post-treatment.

In another application, DEB can be used to treat peripheral diseaseswhich are not treatable by stenting. This is particularly true forvessels below the knee in which the vessels are small and the stentstruts break under the torque.

One possible non-vascular application of drug eluting balloon islocalized chemotherapy. Balloon catheter can be coated with anticanceragent and introduced to cancerous tissue.

Balloons for angioplasty are categorized as high pressure balloons. Astandard balloon consists of a cylindrical body, two conical tapers, andtwo necks. The particular angles and shapes of the balloon can becustomized depending on the application and particularities of thephysiology. High pressure balloons are also used to dilate constrictionsand blockages in other areas such as the esophagus, biliary-duct,urethra, fallopian-tube, heart-valve, tear-duct and carpel-tunneldilation. Other applications for high pressure balloons includepositioning, occlusion, light therapy, heat transfer and endovasculargraft delivery.

High pressure balloons are made from noncompliant or low-compliantmaterials (expand only 5-10%) which have controllable size and shape.Thin-walled, these balloons exhibit high tensile strength withrelatively low elongation. Currently most high pressure balloons aremade from PET or nylon. PET has high tensile strength with a maximumpressure rating. It can be molded to have ultra thin walls (5-50 mm)with diameters from 0.5-50 mm. Nylon is softer and can be easilyrefolded for easier withdrawal into the guiding catheter. Both materialshave demonstrated compatibility to coatings which provide lubricity,abrasion and puncture resistance, conductivity, thrombogenicity, drugrelease, and reflectivity, among other characteristics.

The rated pressure for angioplasty is 2-20 atm. Larger diameter balloonshave a lower rated pressure as the stress in the balloon wall increaseswhen inflated to the nominal diameter. PTCA balloon catheters areusually 2-4 mm in diameter, 10-40 mm in length and have a rate pressureof 10-20 atm. PTA balloon catheters are usually 4-14 mm in diameter and20-200 mm in length and have a rate pressure of 8-20 atm.

Formulations

The oligofluorinated oligomer (e.g., a branched or linearoligofluorinated oligomer) or a branched compound including waterinsoluble segments, preferably the branched compound, and thebiologically active agent of the invention can be formulated as ahomogenous solid or solution, solution dispersion (single or multiphase). The conformational arrangement and compatibility of thebiologically active agent and oligofluorinated oligomer (e.g., abranched or linear oligofluorinated oligomer) or branched compoundincluding water insoluble segments will guide the efficacy offormulation based on release profile, and solubility enhancing effect.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how themethods and compounds claimed herein are performed, made, and evaluated,and are intended to be purely exemplary of the invention and are notintended to limit the scope of what the inventors regard as theirinvention.

Acronyms

The following acronyms denote the listed compounds.BAL poly(difluoromethylene), α-fluoro-ω-(2-hydroxyethyl)CDCl₃ deuterated chloroformDBDL dibutyltin dilaurateDCM dichloromethaneDIC diisopropylcarbodiimideDMAc dimethylacetamideDMAP 4-(dimethylamino)pyridineDMF dimethylformamideDMSO dimethylsulphoxideEtO ethylene oxideHCl hydrochloric acidKBr potassium bromideKD dansyl labelled lysineLDI lysine diisocyanateMeOH methanolNaOH sodium hydroxideN₂ nitrogen gasPBS phosphate buffer solutionPCL polycaprolactonePTMO polytetramethylene oxidePTX paclitaxelSA salicylic acidTEA triethylamineTHF tetrahydrofuranTMX m-tetramethylxylene diisocyanate

EXAMPLES Example 1 Synthesis and Characterization of Compound 1(Oligofluoro-Ester)

PTMO (15.0 g, 14 mmol) was reacted with LDI (5.9 g, 28 mmol) in DMAc (80mL) in the presence of DBDL catalyst, at 70° C. for two hours under N₂.Perfluoroalcohol (13.15 g, 31 mmol) was dissolved in DMAc (25 mL), addedto the reaction, and stirred at room temperature overnight under N₂. Theproduct (Compound 1) was purified by solvent extraction and cationicSPE. GPC (dioxane mobile phase): retention time of 25 minutes. ¹H NMR(400 MHz, CDCl₃) δ (ppm) 4.24-4.46 (—CH₂—O, BAL), 3.94-4.13 (—CH₂—O—CO,PTMO), 3.74 (CH₃, LDI), 3.28-3.50 (CH₂—O, PTMO), 2.98-3.28 (CH ₂—NH,LDI), 2.29-2.60 (—CH₂—CF₂—, BAL), 1.16-1.96 (PTMO and LDI CH₂). IRanalysis was in accordance with the chemical structure: 3318 cm⁻¹ (N—H)H-bonded, 2930 cm⁻¹ (C—H), 2848 cm⁻¹ (C—H), 1712 cm⁻¹ (C═O) urethaneamide, 1524 cm⁻¹ (C—N), 1438 cm⁻¹ (C—N), 1356 cm⁻¹ (C—O), 1400-1000 cm⁻¹(C—F). Elemental analysis: 20% F. DSC analysis: T_(g)=−69° C. Compound 1was further purified by dissolving in MeOH and dialyzing for three daysusing 1000 MWCO regenerated cellulose membranes.

Example 2 Synthesis and Characterization of Compound 2(Oligofluoro-Acid)

Compound 1 was dissolved in MeOH and treated with 1N NaOH. The product(Compound 2) was neutralized with 1N HCl, precipitated in water, anddried. GPC (dioxane mobile phase): retention time of 25 minutes. ¹H NMR(400 MHz, CDCl₃) δ (ppm) 4.26-4.48 (—CH₂—O, BAL), 3.96-4.23 (—CH₂—O—CO,PTMO), 3.30-3.52 (CH₂—O, PTMO), 3.07-3.22 (CH ₂—NH, LDI), 2.36-2.55(—CH₂—CF₂—, BAL), 1.14-1.94 (PTMO and LDI CH₂). IR analysis was inaccordance with the chemical structure: 3318 cm⁻¹ (N—H) H-bonded, 2930cm⁻¹ (C—H), 2848 cm⁻¹ (C—H), 1712 cm⁻¹ (C═O) urethane amide, 1524 cm⁻¹(C—N), 1438 cm⁻¹ (C—N), 1356 cm⁻¹ (C—O), 1400-1000 cm⁻¹ (C—F). Compound2 was further purified by dissolving in MeOH and dialyzing for threedays using 1000 MWCO regenerated cellulose membranes.

Example 3 Synthesis and Characterization of Compound 3 (DansylOligofluoro)

Compound 2 (2.0 g, 1.71 mmol acid) was dissolved in anhydrous DMF (25mL). The solution was chilled, DIC (0.215 g, 1.71 mmol) was added andthe solution was stirred for 2 hours at room temperature under N₂. TEA(0.345 g, 3.41 mmol) and dansyl-labelled lysine (KD) (0.718 g, 1.71mmol) in anhydrous DMF (9 mL) were added to the activated Compound 2,and the solution was kept well stirred for 12 hours at room temperatureunder N₂. The product (Compound 3) was purified with cationic andfluorous SPE, and recovered by rotary evaporation. GPC (dioxane mobilephase): no free KD was detected, and the polymer peak had strong UVabsorbance. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.14-8.59 (aromatic H, KD)4.46-4.66 (CH₂—N, KD), 4.28-4.48 (—CH₂—O, BAL), 3.90-4.17 (—CH₂—O—CO,PTMO), 3.31-3.54 (CH₂—O, PTMO), 3.06-3.26 (CH ₂—NH, LDI), 2.81-3.00(CH₃, KD) 2.32-2.58 (—CH₂—CF₂—, BAL), 1.08-1.94 (CH₂, PTMO, LDI and KD).High performance liquid chromatography (HPLC) analysis of Compound 3:samples ranging in concentration from 0.0005 to 50 mg/mL in MeOH wereinjected and analyzed using MeOH/pH 9 buffer mobile phase. Free KD(standard solution) eluted at 21 minutes, and Compound 3 eluted at 35minutes with no evidence of free KD contamination.

Example 4 Synthesis and Characterization of Compound 4 (SiliconeOligofluoro)

Hydroxy terminated PDMS (10 g, 13.8 mmol) was reacted with LDI (5.848 g,28 mmol) in DMAc (80 mL) in the presence of DBDL catalyst, at 70° C. fortwo hours under N₂. Perfluoroalcohol (12.745 g, 30 mmol) was dissolvedin DMAc (32 mL), added to the reaction, and stirred at room temperatureovernight under N₂. GPC (THF mobile phase): retention time of 25.5minutes. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 4.26-4.48 (—CH₂—O, BAL),3.93-4.09 (—CH₂—O—CO, PDMS), 3.74 (CH₃, LDI), 3.08-3.26 (CH ₂—NH, LDI),2.33-2.60 (—CH₂—CF₂—, BAL), 1.61-1.76 (—Si—O—CH₂, PDMS), 1.13-1.93 (CH₂,LDI), 0.49-0.60 (CH₂—CH—CH ₂, PDMS), 0.025-0.36 (CH₃, PDMS). DSCanalysis: T_(g)=−40° C. Elemental Analysis: 21.2% F.

Example 5 Synthesis and Characterization of Compound 5 (BPH Oligofluoro)

Neopentyl glycol phthalic anhydride based polyester diol (BPH, 10.0 g,10 mmol) was reacted with LDI (4.24 g, 20 mmol) in anhydrous DMAc (70mL) in the presence of DBDL catalyst, at 70° C. for two hours under N₂.Perfluoroalcohol (9.24 g, 22 mmol) was dissolved in anhydrous DMAc (25mL), added to the reaction, and stirred at room temperature overnightunder N₂. The product (Compound 5) was purified by solvent extractionand cationic SPE. GPC (THF mobile phase): retention time of 25.4minutes. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.41-7.79 (aromatic H, BPH),4.25-4.44 (—CH₂—O, BAL), 4.05-4.21 (—CH₂—O, BPH), 3.67-3.79 (—CH₃, LDI),3.06-3.25 (CH₂—NH, LDI), 2.32-2.56 (—CH₂—CF₂—, BAL), 1.26-1.90 (CH₂,LDI), 0.86-1.11 (—CH₃, BPH). Surface analysis (XPS): 31.4% F. Elementalanalysis: 15.64% F. DSC analysis: T_(g)=25° C. Contact angle (wateradvancing): 106°. Texture analysis: 1.8 g. Compound 5 was furtherpurified by dissolving in acetone and dialyzing for three days using1000 MWCO regenerated cellulose membranes.

Example 6 Synthesis and Characterization of Compound 6 (PEG Oligofluoro)

PEG (7.65 g, 7.65 mmol) was reacted with LDI (3.25 g, 15.3 mmol) inanhydrous THF (54 mL) in the presence of DBDL catalyst, at 70° C. fortwo hours under N₂. Perfluoroalcohol (7.07 g, 16.8 mmol) was dissolvedin anhydrous THF (18 mL), added to the reaction, and stirred at roomtemperature overnight under N₂. The product (Compound 6) was purified byprecipitation and cationic SPE. GPC (THF mobile phase): retention timeof 24 minutes. ¹H NMR (300 MHz, CDCl₃) δ (ppm) 4.25-4.44 (—CH₂—O, BAL),4.08-4.15 (—CH₂—O—CO, PEG), 3.70-3.75 (—CH₃, LDI), 3.55-3.77 (—CH₂,PEG), 3.10-3.30 (CH₂—NH, LDI), 2.32-2.60 (—CH₂—CF₂—, BAL), 1.20-1.90(CH₂, LDI). DSC analysis: T_(g)=−45.5° C., T_(m)=21.7° C. Contact angleanalysis (water advancing): 108.7°. Compound 6 was further purified bydissolving in acetone and dialyzing for three days using 1000 MWCOregenerated cellulose membranes.

Example 7 Synthesis and Characterization of Compound 7 (NPG542Oligofluoro)

Neopentyl glycol (NPG, 3.0 g, 28.8 mmol) was reacted with LDI (7.63 g,36 mmol) in anhydrous THF (133 mL) in the presence of DBDL catalyst, at70° C. for two hours under N₂. Perfluoroalcohol (6.65 g, 15.8 mmol) wasdissolved in anhydrous THF (83 mL), added to the reaction, and stirredat room temperature overnight under N₂. The product (Compound 7) waspurified by precipitation and cationic SPE. GPC (THF mobile phase):retention time of 26 minutes. ¹H NMR (300 MHz, CDCl₃) δ (ppm) 4.23-4.48(—CH₂—O, BAL), 3.85-4.10 (—CH₂—O—CO, NPG), 3.70-3.73 (—CH₃, LDI),3.10-3.20 (CH₂—NH, LDI), 2.30-2.58 (—CH₂—CF₂—, BAL), 1.25-1.85 (CH₂,LDI), 0.80-1.05 (CH₃, NPG). Surface analysis (XPS): 18.75% F. Elementalanalysis: 14.46% F. DSC analysis: T_(g)=−3° C., T_(m)=161° C. Contactangle analysis (water advancing): 106.9° C. Texture analysis: 1 g.Compound 7 was further purified by dissolving in acetone and dialyzingfor three days using 1000 MWCO regenerated cellulose membranes.

Example 8 Synthesis and Characterization of Compound 8 (PEGAOligofluoro)

Poly(diethylene adipate) (PEGA, 7.45 g, 2.98 mmol) was reacted with LDI(1.26 g, 5.96 mmol) in anhydrous DMAc (43.5 mL) in the presence of DBDLcatalyst, at 70° C. for two hours under N₂. Perfluoroalcohol (2.75 g,6.55 mmol) was dissolved in anhydrous DMAc (7 mL), added to thereaction, and stirred at room temperature overnight under N₂. Theproduct (Compound 8) was purified by precipitation and cationic SPE. GPC(THF mobile phase): retention time of 22.5 minutes. ¹H NMR (300 MHz,CDCl₃) δ (ppm) 4.30-4.40 (—CH₂—O, BAL), 4.20-4.30 (—CH₂—O—CO, PTMO;—NH—OCO—O—CH ₂—CH₂—, PEGA), 3.75 (CH₃, LDI), 3.58-3.72 (—O—CH ₂—CH ₂—O—,PEGA), 3.12-3.24 (CH ₂—NH, LDI), 2.30-2.70 (—CH₂—CF₂—, BAL; —OCO—O—CH₂—, PEGA), 1.25-2.0 (CH₂ LDI; —CH₂CH ₂CH₂—, PEGA). Surface analysis(XPS): 41.06% F. Elemental analysis: 25.76% F. Contact angle analysis(water advancing): 118.5°. DSC analysis: T_(g)=−43° and 156°. Viscosityanalysis (37° C.): 144 Pa·s. Texture analysis: 66 g. Compound 8 wasfurther purified by dissolving in acetone and dialyzing for three daysusing 1000 MWCO regenerated cellulose membranes.

Example 9 Synthesis and Characterization of Compound 9 (HPCN TMXOligofluoro)

Hexamethylene polycarbonate diol (HPCN, 25.0 g, 12.5 mmol) was reactedwith LDI (6.10 g, 25 mmol) in anhydrous DMAc (150 mL) in the presence ofDBDL catalyst, at 70° C. for two hours under N₂. Perfluoroalcohol (11.55g, 27.5 mmol) was dissolved in anhydrous DMAc (29 mL), added to thereaction, and stirred at room temperature overnight under N₂. Theproduct (Compound 9) was purified by solvent extraction and cationicSPE. GPC (dioxane mobile phase): retention time of 22.6 minutes. ¹H NMR(300 MHz, CDCl₃) δ (ppm) 7.2-7.45 (—CH, TMX), 4.30-4.43 (—CH₂—O, BAL),4.04-4.20 (—CH₂—CH ₂—O—CO, HPCN), 3.90-4.03 (—CH ₂—O—CO—NH, HPCN),2.25-2.55 (—CH₂—CF₂—, BAL), 1.13-1.80 (CH₂, HPCN; CH₃, TMX). Elementalanalysis: 10.5% F. DSC analysis: T_(g)=−32.2° C., T_(m)=147° C. Surfaceanalysis (XPS): 33.17% F. Viscosity analysis (37° C.): 360 Pa·s. Textureanalysis: 170 g. Compound 9 was further purified by dissolving inacetone and dialyzing for three days using 1000 MWCO regeneratedcellulose membranes.

Example 10 Synthesis and Characterization of Compound 10 (EGOligofluoro)

Ethylene glycol (EG, 1.5 g, 24.2 mmol) was reacted with LDI (10.3 g,48.4 mmol) in anhydrous THF (60 mL) in the presence of DBDL catalyst, at70° C. for two hours under N₂. Perfluoroalcohol (22.4 g, 53.2 mmol) wasdissolved in anhydrous THF (56 mL), added to the reaction, and stirredat room temperature overnight under N₂. The product (Compound 10) waspurified by precipitation and cationic SPE. GPC (THF mobile phase):retention time of 27 minutes. ¹H NMR (300 MHz, CDCl₃) δ (ppm) 4.23-4.48(—CH₂—O, BAL), 4.10-4.25 (—CH₂—O—CO, EG), 3.75 (—CH₃, LDI), 3.10-3.28(CH₂—NH, LDI), 2.36-2.60 (—CH₂—CF₂—, BAL), 1.25-1.85 (CH₂, LDI). Surfaceanalysis (XPS): 36.87% F. Elemental analysis: 27.51% F. DSC analysis:T_(g)=−3° C. Contact angle analysis (water advancing): 130.7°. Viscosityanalysis (37°): 2397 Pa·s. Texture analysis: 29.1 g.

Example 11 Synthesis and Characterization of Compound 11 (HPHOligofluoro)

1,6-hexanediol-phthalic anhydride based polyester diol (HPH, 20.0 g, 10mmol) was reacted with LDI (4.24 g, 20 mmol) in anhydrous THF (122 mL)in the presence of DBDL catalyst, at 70° C. for two hours under N₂.Perfluoroalcohol (9.24 g, 22 mmol) was dissolved in anhydrous THF (23mL), added to the reaction, and stirred at room temperature overnightunder N₂. The product (Compound 11) was purified by precipitation andcationic SPE. GPC (THF mobile phase): retention time of 23.8 minutes. ¹HNMR (300 MHz, CDCl₃) δ (ppm) 7.52-7.68 (—CH, aromatic ring HPH),4.30-4.40 (—CH₂—O, BAL), 4.10-4.22 (—CH ₂—O—CO, HPH), 4.0-4.08(—CH₂—COO—NH—, HPH), 3.70-3.75 (—CH₃, LDI), 3.10-3.21 (CH₂—NH, LDI),2.32-2.52 (—CH₂—CF₂—, BAL), 1.24-1.85 (CH₂, LDI and HPH). DSC analysis:T_(g)=−13° C. Contact angle analysis (water advancing): 119.1°. Surfaceanalysis (XPS): 40.74% F. Elemental analysis: 9.18% F. Viscosityanalysis (37° C.): 896 Pa·s. Texture analysis: 113.9 g. Compound 11 wasfurther purified by dissolving in acetone and dialyzing for three daysusing 1000 MWCO regenerated cellulose membranes.

Example 12 Synthesis and Characterization of Compound 12 (P3611Oligomer)

Polyalkoxylated polyol (P3611) (1 g, 3.8 mmol) was reacted with LDI(2.391 g, 11.28 mmol) in DMAc (17 mL) in the presence of DBDL catalyst,at 70° C. for two hours under N₂. Perfluoroalcohol (5.211 g, 12.4 mmol)was dissolved in DMAc (13 mL), added to the reaction, and stirred atroom temperature overnight under N₂. GPC (THF mobile phase): retentiontime of 23 minutes. ¹H NMR (300 MHz, CDCl₃) δ (ppm) 4.25-4.51 (—CH₂—O,BAL), 3.93-4.07 (—CH₂—O—CO, P3611), 3.73 (CH₃, LDI), 3.05-3.25 (CH ₂—NH,LDI), 2.31-2.57 (—CH₂—CF₂—, BAL), 1.21-1.93 (CH₃—CH₂—, P3611, and CH₂,LDI), 0.79-0.95 (CH₃, P3611). Elemental Analysis: 33% F.

Example 13 Synthesis and Characterization of Compound 13 (HexafluoroPentanediol Oligofluoro)

2,2,3,3,4,4-Hexafluoro-1,5-pentanediol (HPD, 1.04 g, 4.9 mmol) wasreacted with LDI (2.07 g, 9.75 mmol) in anhydrous DMAc (20 mL) in thepresence of DBDL catalyst at 70° C. for two hours under N₂. Methanol(417 μL) was added to the reaction, and stirred at room temperatureovernight under N₂. Solvent was removed and the product (Compound 12)was purified by cationic SPE. GPC analysis: the product was dissolved indioxane and run on a GPC system with a polystyrene column and UVdetector. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 4.53-4.75 (—CH_—CF₂, HPD),4.30-4.40 (—CH, LDI), 3.70 (—CH₃, LDI), 3.60-3.65 (CH₃—O, MeOH),3.10-3.25 (CH₂—NH, LDI), 1.25-1.85 (CH₂, LDI). Compound 12 was blendedinto a Carbothane 85A base polymer as a 5 wt % additive, using DMAcsolvent to make a 0.1 g/mL solution. Films of the blend were cast inTeflon molds, and dried at 50° C. for 24 hours, followed by drying undervacuum at 50° C. for 24 hours. Surface analysis of film blend (XPS):1.78% F.

Example 14 Synthesis and Characterization of Compound 14 (PerfluoroDodecanediol Oligofluoro)

1H,1H,12H,12H-Perfluoro-1,12-dodecanediol (PDD, 1.02 g, 1.81 mmol) wasreacted with LDI (0.77 g, 3.63 mmol) in anhydrous DMAc (20 mL) in thepresence of DBDL catalyst at 70° C. for two hours under N₂. Methanol(158 μL) was added to the reaction, and stirred at room temperatureovernight under N₂. Solvent was removed and the product (Compound 14)was purified by cationic SPE. GPC analysis: the product was dissolved indioxane and run on a GPC system with a polystyrene column and UVdetector. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 4.53-4.75 (—CH₂—CF₂, PDD),4.30-4.40 (—CH, LDI), 3.70 (—CH₃, LDI), 3.60-3.65 (CH₃—O, MeOH),3.10-3.25 (CH₂—NH, LDI), 1.25-1.85 (CH₂, LDI). Compound 14 was blendedinto a Carbothane 85A base polymer as a 5 wt % additive, using DMAcsolvent to make a 0.1 g/mL solution. Films of the blend were cast inTeflon molds, and dried at 50° C. for 24 hours, followed by drying undervacuum at 50° C. for 24 hours. Surface analysis of film blend (XPS):35.63% F.

Example 15 Synthesis and Characterization of Compound 15(Bis-Hydroxyphenyl Hexafluoropropane)

2,2-Bis(4-hydroxyphenyl) hexafluoropropane (BHP, 1.08 g, 3.21 mmol) wasreacted with LDI (1.37, 6.44 mmol) in anhydrous DMAc (20 mL) in thepresence of DBDL catalyst at 70° C. for four hours under N₂. Methanol(290 μL) was added to the reaction, and stirred at room temperatureovernight under N₂. The product (Compound 15) was isolated by removingsolvent. GPC analysis: the product was dissolved in dioxane and run on aGPC system with a polystyrene column and UV detector. ¹H NMR (400 MHz,DMSO) δ (ppm) 6.98-7.03 (—CH—CCF₃, BHP), 6.75-6.83 (—CH—CO, BHP),4.53-4.75 (NH, LDI), 4.30-4.40 (—CH, LDI), 3.65 (—CH₃, LDI), 3.45-3.51(CH₃—O, MeOH), 3.10-3.25 (CH₂—NH, LDI), 1.25-1.85 (CH₂, LDI). Compound15 was blended into a Carbothane 85A base polymer as a 5 wt % additive,using DMAc solvent to make a 0.1 g/mL solution. Films of the blend werecast in Teflon molds, and dried at 50° C. for 24 hours, followed bydrying under vacuum at 50° C. for 24 hours. Surface analysis of filmblend (XPS): 3.82% F.

Example 16 Synthesis and Characterization of Compound 16 (HEMAConjugated Oligofluoro)

Compound 2 (10.0 gram, ˜8 mmol acid), DMAP (0.488 gram, 4 mmol), HEMA(6.247 gram, 48 mmol), and DCM (50 mL) were added to a 250 mL flask, andstirred until all compounds were dissolved. EDC (4.600 gram, 24 mmol)was added to the DCM solution, and once the EDC was dissolved, thesolution was stirred at room temperature for 24 hours under N₂ andprotected from light. The reaction mixture was reduced to a viscousliquid by rotary evaporation (25° C.) and washed three times with water(3×400 mL). The washed product was dissolved in diethyl ether (100 mL,100 ppm BHT), and water was removed by mixing the solution with MgSO₄for 1 hour. The solution was clarified by gravity filtration into a 250mL flask, and the solvent was removed by rotary evaporation (25° C.).The product (Compound 16) was re-dissolved in DMF and was purified usingfluorous SPE (F-SPE) and recovered by rotary evaporation. ¹H NMR (300MHz, CDCl₃) δ (ppm) 6.09-6.15 (HEMA vinyl H), 5.58-5.63 (vinyl H, HEMA),4.83-5.78 (—CH₂), 4.27-4.49 (CH₂—O, BAL; CH₂, HEMA), 4.01-4.15(CH₂—OCO—, PTMO), 3.75 (small CH₃ signal), 3.31-3.50 (CH₂—O—, PTMO),3.07-3.23 (CH ₂—NH, PTMO), 2.36-2.56 (CH₂—CF₂—, BAL), 1.91-1.96 (CH₃,HEMA) 1.27-1.74 (CH₂, PTMO and LDI). GPC analysis (dioxane mobilephase): retention time of 26.5 minutes. No free HEMA monomer detected inthis analysis. IR analysis: 1634 cm⁻¹ (C═C).

Example 17 Synthesis and Characterization of Compound 17 (FEO1Oligofluoro)

PTMO (10 g, 0.0097 mol, degassed) was dissolved in anhydrous DMAc (50mL). Lysine diisocyanate (4.11 g, 0.020 mol, distilled) and DBDLcatalyst was dissolved in anhydrous DMAc (25 mL) and was added dropwiseto the PTMO solution. The pre-polymer reaction was maintained at 60-70°C. for two hours under a nitrogen atmosphere. The perfluoroacrylate(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11 heptadecafluoro-2-hydroxyundecylacrylate) (FEO1, 12.058 g, 0.022 mol) was dissolved in DMAc (25 mL) withDBDL and added dropwise to the pre-polymer solution, stirred overnightunder N₂ at room temperature. The product was precipitated in water (2L), re-dissolved in diethyl ether (100 mL, 100 ppm BHT), dried withMgSO₄ and filtered. The ether solution was dropped into hexane (400 mL)to precipitate the product and extract un-reacted reagent. The hexanewas decanted and the solvent extraction procedure was repeated twice.The purified product (Compound 17) was dissolved in diethyl ether (50mL), and the solvent removed by rotary evaporation at room temperature.¹H NMR (400 MHz, CDCl₃) δ (ppm) 6.40-6.52 (vinyl H, FEO1), 6.09-6.23(vinyl H, FEO1), 5.80-5.95 (vinyl H, FEO1), 4.15-4.53 (C—H, FEO1; O—CH₂—FEO1), 4.00-4.15 (—CH₂—O—CO, PTMO), 3.75 (CH₃, LDI), 3.31-3.50 (CH₂—O,PTMO), 3.05-3.25 (CH ₂—NH, LDI), 2.35-2.61 (—CH₂—CF₂—, FEO1), 1.25-1.73(CH₂, PTMO and LDI). GPC analysis (dioxane mobile phase): retention timeof 26 minutes. No free FEO1 monomer detected in this analysis. IRanalysis: 1634 cm⁻¹ (C═C).

Example 18 Synthesis and Characterization of Compound 18 (FEO3Oligofluoro)

PTMO (10 g, 0.0097 mol, degassed) was dissolved in anhydrous DMAc (50mL). Lysine diisocyanate (4.241 g, 0.02 mol, distilled) and dibutyltindilaurate catalyst was dissolved in anhydrous DMAc (22 mL) and was addeddropwise to the PTMO solution. The pre-polymer reaction was maintainedat 60-70° C. for two hours under N₂. The perfluoroacrylate(3-(perfluoro-3-methylbutyl)-2-hydroxypropyl methacrylate) (FEO3, 9.068g, 0.022 mol) was dissolved in DMAc (23 mL) with dibutyltin dilaurateand added dropwise to the pre-polymer solution. The reactor was stirredovernight at room temperature under N₂. The product was precipitated inwater (2 L), re-dissolved in diethyl ether (100 mL, 100 ppm BHT), driedwith MgSO₄ and filtered. The ether solution was dropped into hexane (400mL) to precipitate the product and extract un-reacted reagent. Thehexane was decanted and the solvent extraction procedure was repeatedtwo times. The purified product (Compound 18) was dissolved in diethylether (50 mL), and the solvent removed by evaporation in a flow hood atroom temperature. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 6.10-6.16 (vinyl H,FEO3), 5.66-5.89 (vinyl H, FEO3), 4.27-4.41 (—O—CH₂—, FEO3), 4.15-4.27(—O—CH₂—, FEO3) 4.00-4.14 (—CH₂—O—CO, PTMO), 3.75 (CH₃, LDI), 3.27-3.52(CH₂—O, PTMO), 3.05-3.21 (CH ₂—NH, LDI), 2.34-2.61 (—CH₂—CF₂—, FEO3),1.90-1.99 (CH₃, FEO3), 1.22-1.90 (CH₂, LDI and PTMO). GPC analysis(dioxane mobile phase): retention time of 26.5 minutes. No free FEO3monomer detected in this analysis. IR analysis: 1634 cm⁻¹ (C═C).

Example 19 Synthesis and Characterization of Compound 19 (TrisOligofluoro)

Method A: EDC Conjugation of Tris

Compound 2 (10 g, 4.4 mmol), EDC, and DMAP (in a 1:6:0.5 molar ratio ofacid groups:EDC:DMAP) were dissolved in anhydrous DMF (200 mL). Tris (ina 1.1:1 molar ratio of Tris:acid groups) was added to the reactionmixture. This solution was reacted under N₂ for 24 hours at roomtemperature. The DMF solvent was evaporated at 40° C. The viscousresidual was extracted with diethyl ether (3×100 mL) at roomtemperature. EDC and Tris are insoluble in cold ether. The clear ethersolution was evaporated. The white viscous product (Compound 19-a) wasdried under vacuum at 40° C. overnight. Elemental analysis: 25.57% F. IRanalysis: 3330 cm⁻¹ (O—H), 1110 cm⁻¹ (C—OH), 1160 cm⁻¹ (C—F), 1220 cm⁻¹(C—O—C). ¹H NMR (300 MHz, CDCl₃) δ (ppm) 2.38 (C_(Tris)CH₂OH), 1.73(C_(Tris)—NH). Determination of the OH number: the hydroxyl content ofCompound 19-a (which is unique to the pendent Tris) was determined byreacting Compound 19-a with excess acetic anhydride in pyridine,followed by back-titration with potassium hydroxide base usingphenolphthalein as an indicator. Result: OH number 2.4113 mmol/g.

Method B: K₂CO₃ Conjugation of Tris

Compound 1 (3.05 g, ˜2.6 mmol) was dissolved in anhydrous methanol (100mL). A mixture of tris hydroxymethyl aminoethane (Tris, 0.63 g, 5.2mmol) and anhydrous potassium carbonate (0.72 g, 5.2 mmol) was added.This reaction mixture was refluxed at 45° C. for seven days. Thereaction mixture was cooled, and the solution was purified usingcationic exchange and fluorous solid phase reaction. The final product(Compound 19-b) was dried under vacuum for 48 hours (50° C.). ¹H NMR(300 MHz, CDCl₃) δ (ppm) 4.25-4.50 (—CH₂—O, BAL), 3.95-4.20 (—CH₂—OCO—,PTMO), 3.75 (reduced CH₃ signal, LDI), 3.57-3.83 (CH₂, Tris), 3.30-3.56(—CH₂O, PTMO), 3.04-3.28 (—CH ₂NH—, PTMO), 2.29-2.59 (CH₂CF₂—, BAL),1.17-1.97 (—CH₂—, PTMO and LDI). HPLC analysis (Reversed phase HPLC, C18column, methanol and pH 9 PBS mobile phase (gradient)): elution time of34.6 minutes. Compound 19-b was blended into a Carbothane 85A basepolymer as a 5 wt % additive, using DMAc solvent to make a 0.1 g/mLsolution. Films of the blend were cast in Teflon molds, and cured at 50°C. for 24 hours, followed by drying under vacuum at 50° C. for 24 hours.The air-contacting surface of the film was analyzed by XPS, using a 90°take-off angle. Elemental analysis: Carbothane 0% F; Carbothane+5 wt %Compound 19-b 36.3% F. Contact angle analysis: Compound 19-b was blendedinto Carbothane 85A and ethylene-co-vinyl acetate (EVA) base polymer as5 wt % mixtures, using solvent casting techniques. Contact angleanalysis was performed using water EVA. 105°+/−2° (hydrophobic),EVA+Compound 19-b: 15°+/−2° (hydrophilic). Carbothane 85A: 102°+/−4°(hydrophobic), Carbothane+Compound 19-b: 18°+/−5° (hydrophilic).

Example 20 Synthesis and Characterization of Compound 20 (Tris-BrOligofluoro)

Compound 19 (Tris oligofluoro) (10 g, 4.0 mmol) (dried previously) andTEA (in a 1.2:1 molar ratio of TEA:OH groups) were dissolved inanhydrous CH₂Cl₂ (50 mL) under N₂. The solution was cooled in anice-water bath. A stoichiometric quantity of 10% BIBB/CH₂Cl₂ solutionwas added dropwise to Compound 19/CH₂Cl₂ solution under a nitrogenatmosphere. The mixture was stirred for 24 hours at room temperature andwas then filtered to remove the TEA-HBr salt. The filtrate was washedwith water (10 mL) three times. The CH₂Cl₂ was evaporated at roomtemperature. A pale brown viscous solid product (Compound 20) wasobtained. Elemental analysis: 17.42% F, 13.65% Br. ¹H NMR (300 MHz,CDCl₃) δ (ppm) 2.05 (C(CH ₃)₂Br).

Example 21 Synthesis and Characterization of Compound 21 (Tris-PHEMA-BrOligofluoro)

Compound 20 (Tris-Br oligofluoro) (2.5 g, 1 mmol) was dissolved in DMF(10 mL). CuBr (0.143 g, 1 mmol) and HMTETA (0.253 g, 1.1 mmol) wereadded into the solution. The flask was connected to a vacuum line andwas freeze-thawed three times by liquid nitrogen. The flask was filledwith ultrahigh-purity nitrogen and freshly distilled HEMA (2.86 g, 22mmol) was added. The flask was heated in an oil bath to 50° C. for 20hours. The polymerization was stopped by cooling the flask in ice water.DMF was evaporated from the solution at 40° C. The viscous solid wasdissolved in THF and filtered through a silica gel column to remove thecatalyst. After evaporating THF from the filtrate at room temperature,the solid product (Compound 21) was dried under vacuum at 40° C.overnight. Elemental analysis: 10.21% F; 0.28% Br. ¹H NMR (300 MHz,DMSO) δ (ppm) 4.80 (CH₂OH, HEMA), 3.92 (COOCH ₂, HEMA), 3.60 (CH ₂OH,HEMA), 1.79 (CH ₂CCH₃, HEMA), 0.80 (CH₂CCH ₃, HEMA). The average(polystyrene equivalent) molecular weight was recorded as 9.01×10⁴ g/molwith polydispersity of 1.65. The weight average MW of the final productwas substantially larger than Compound 20. This data indicated asuccessful polymerization of the final product. Based on OH titration,the average degree of polymerization can be determined for the PHEMAportion of the molecule. The theoretical OH number was 6.366 mmol/g, andthe titrated value was 6.386 mmol/g. Based on the OH number, the HEMAwas quantitatively incorporated and the average degree of polymerizationfor the PHEMA branch was 21.7.

Example 22 Synthesis and Characterization of Compound 22 (Tris-PMAA-BrOligofluoro)

Tert-butyl methacrylate (tBMA, 2.10 g, 15 mmol), CuBr (0.149 g, 1 mmol),and xylene (4 mL) were added to a flask. The flask was scaled with arubber septum and cooled in ice water. Ultrahigh-purity nitrogen waspurged through the mixture for 15 minutes. Then, HMTETA (previouslypurged with nitrogen; 0.46 g, 2.0 mmol) was added by syringe. After thesolution became clear and light green in color, a solution of Compound20 (0.5858 g, 1 mmol of Br group) in acetone (5 mL) was added. The flaskwas heated in an oil bath to 70° C. overnight. The polymerization wasstopped by cooling the flask in ice water. The solution was diluted withTHF (20 mL) and filtered through a silicon gel column to remove thecatalyst. The filtrate was precipitated in water, and the solid polymerwas dried under vacuum at 30° C. overnight. The solid polymer (1 g) wasdissolved into a solution of CHCl₃ (9 mL) and CF₃COOH (1 mL). Thesolution was stirred at room temperature for 20 hours. The polymerbecame a gel-like semi solid in the solution. The solvent was removed byfiltration, and the solid was washed with CHCl₃ twice and filtered. Allliquid residuals were removed under vacuum at room temperature. Thesolid product (Compound 22) was dried under vacuum at 40° C. overnight.The number of COOH titrated was 8.8592 mmol/g. Based on titrationresults and the stoichiometry, the tBMA conversion was determined to be96.7%, and the average degree of polymerization of the PMAA branchcalculated was 14.6.

Example 23 Synthesis and Characterization of Compound 23 (Tris-PVP-BrOligofluoro)

1-Vinyl-2-pyrrolidone (VP, 3.33 g, 30 mmol), Compound 20 (1 mmol), andCuBr (0.143 g, 1 mmol) were added to a flask. The flask was sealed witha rubber septum and cooled in ice water. The mixture was purged with N₂for 30 minutes. 2,2′-Dipyridyl (BPY, previously purged with N₂, 0.156 g,1 mmol) was added to the mixture. The flask was heated in an oil bath to100° C. for 20 hours. The polymerization was stopped by cooling theflask in ice water. The solution was diluted with CH₂Cl₂ (200 mL) andfiltered through an alumina column to remove the catalyst. Afterevaporating the CH₂Cl₂ from the filtrate at room temperature, the solidproduct was dried under vacuum at 40° C. overnight. Elemental analysis:0.67% F; 1.10% Br. Based on F and Br content, the VP conversion reached78.6%, translating to an average degree of polymerization for the PVPbranch of 60. ¹H NMR (300 MHz, CDCl₃) δ (ppm) 7.00 (CH₂CH, PVP), 4.92(CH ₂CH, PVP), 3.48 (NCH ₂, PVP), 3.40 (CH ₂OCH ₂, polyurethane), 2.47(COCH₂, PVP), 2.10 (CH₂CH ₂CH₂, PVP), 1.62 (CH₂C{right arrow over(H)}₂C{right arrow over (H)}₂CH₂, polyurethane).

Example 24 Synthesis and Characterization of Compound 24 (AccmerOligofluoro)

Accmer (7.0 g, 7.0 mmol) was reacted with LDI (2.97 g, 14 mmol) inanhydrous DMAc (50 mL) in the presence of DBDL catalyst at 70° C. for 2hours under N₂. Perfluoroalcohol (6.45 g, 15.4 mmol) was dissolved inanhydrous DMAc (16.2 mL), added to the reaction, and stirred at roomtemperature overnight under N₂. The product (Compound 24) was purifiedby cationic SPE. GPC (THF mobile phase): retention time of 25.5 minutes.¹H NMR (300 MHz, CDCl₃) δ (ppm) 4.24-4.46 (—CH₂—O, BAL), 3.94-4.13(—CH₂—O—CO, Accmer), 3.75 (CH₃, LDI), 3.38-3.64 (CH₂—O, Accmer), 3.16(CH ₂—NH, LDI), 2.29-2.60 (—CH₂—CF₂—, BAL), 1.16-1.96 (CH₂, Accmer andLDI), 0.84 (CH₂, Accmer). DSC analysis: T_(g)=−47° C., T_(m)=23° C.Elemental analysis: 17% F. Compound 24 was further purified bydissolving in acetone and dialyzing for three days using 1000 MWCOregenerated cellulose membranes. Elemental analysis: 13.3% F. Compound24 was drop casted onto nylon for surface analysis (XPS): 45% C, 29% F,5% N, 21% O.

Example 25 Synthesis and Characterization of Compound 25 (Accmer TMXOligofluoro)

Accmer (3.0 g, 3.0 mmol) was reacted with TMX (1.466 g, 6.0 mmol) inanhydrous DMAc (25 mL) in the presence of DBDL catalyst at 70° C. for 2hours under N₂. Perfluoroalcohol (2.778 g, 6.0 mmol) was dissolved inanhydrous DMAc (25 mL), added to the reaction, and stirred at roomtemperature overnight under N₂. The product had a GPC (THF mobile phase)retention time of 27 minutes. The product was purified by cationic SPE.¹HNMR analysis was in accordance with the expected chemical structure.¹H-NMR (300 MHz, CDCl₃) δ (ppm) 7.1-7.6 (aromatic-CH₂, TMX), 4.3-4.4(—CH₂—O, BAL; —NH-urethane), 3.9-4.0 (—CH₂—O—CO, Accmer), 3.4-3.8(—CH₂—O—, Accmer), 3.38 (—CH₂—, Accmer), 2.3-2.5 (—CH₂—CF₂—, BAL),1.5-2.0 (—CH₃, TMX), 1.2 (—CH₃, Accmer), 0.9 (—CH₃, Accmer). Elementalanalysis: 17% F. Compound 25 was drop casted onto nylon for surfaceanalysis (XPS): 54% C, 27% F, 3% N, 15% O.

Example 26 Synthesis and Characterization of Compound 26 (Accmer HDIOligofluoro)

Accmer (3.0 g, 3.0 mmol) was reacted with HDI (1.009 g, 6.0 mmol) inanhydrous DMAc (25 mL) in the presence of DBDL catalyst at 70° C. for 2hours under N₂. Perfluoroalcohol (2.778 g, 6.0 mmol) was dissolved inanhydrous DMAc (25 mL), added to the reaction, and stirred at roomtemperature overnight under N₂. The product had a GPC (THF mobile phase)retention time of 25 minutes. The product was purified by cationic SPE.¹HNMR analysis was in accordance with the expected chemical structure.¹H-NMR (300 MHz, CDCl₃) δ (ppm) 4.3-4.4 (—CH₂—O, BAL; —NH-urethane),3.9-4.0 (—CH₂—O—CO, Accmer), 3.5-3.7 (—CH₂—O—, Accmer; NH—COO—,HDI-Accmer urethane), 3.38 (—CH₂—, Accmer), 3.1-3.25 (NH—CH ₂—, HDI),2.3-2.5 (—CH₂—CF₂—, BAL), 1.3-1.6 (—CH₂—, HDI), 0.9 (—CH₃, Accmer).Compound 26 was drop casted onto nylon for surface analysis (XPS): 44%C, 46% F, 3% N, 7% O.

Example 27 Synthesis and Characterization of Compound 27 (Accmer THDIOligofluoro)

Accmer (3.0 g, 3.0 mmol) was reacted with THDI (1.045 g, 6.0 mmol) inanhydrous DMAc (25 mL) in the presence of DBDL catalyst at 70° C. for 2hours under N₂. Perfluoroalcohol (2.778 g, 6.0 mmol) was dissolved inanhydrous DMAc (25 mL), added to the reaction, and stirred at roomtemperature overnight under N₂. The product had a GPC (THF mobile phase)retention time of 25 minutes. The product was purified by cationic SPE.¹HNMR analysis was in accordance with the expected chemical structure.¹H-NMR (300 MHz, CDCl₃) δ (ppm) 4.3-4.4 (—CH₂—O, BAL; —NH-urethane),3.9-4.0 (—CH₂—O—CO, Accmer), 3.4-3.8 (—CH₂—O—, Accmer), 3.38 (—CH₂—,Accmer), 2.3-2.5 (—CH₂—CF₂—, BAL), 1.2 (—CH₃, Accmer), 0.9 (—CH₃,Accmer). Elemental analysis: 12% F. Compound 27 was drop casted ontonylon for surface analysis (XPS): 55% C, 25% F, 3% N, 17% O.

Example 28 Sterilization of Selected Compounds and Balloon Catheter

Selected compounds from Examples 1-27 were weighed into polypropyleneconical tubes capped with lint-free tissue, placed in sterilizationpouches, and were sterilized by EtO. The sterilized compounds wereanalyzed by GPC, and these results were compared to thepre-sterilization profile. No changes were observed for pre and poststerilization samples.

Compound 24 and PTX complex was prepared according to the establishedprotocol, weighed into polypropylene conical tube capped with lint-freetissue, placed in sterilization pouches, and sterilized by EtO. Thesterilized complex was analyzed by GPC and HPLC and compared to itsprofile pre sterilization. No changes observed were observed in bothCompound 24 and PTX post sterilization.

Balloon catheters coated with Compound 1, Compound 24, and Compound24+PTX were also sterilized by EtO. Sterilized and non-sterilizedballoon catheters were analyzed by GPC, and pre- and post sterilizationmolecular weight profile compared. MW pre-sterilization: Compound 1:8655, Compound 24: 4212, Compound 24+PTX: 4212. MW post sterilization:Compound 1: 8960; Compound 24: 4841, Compound 24+PTX: 4849. PTX HPLCretention time (min): Pre-sterilization: 12.202, post sterilization:12.192.

Example 29 Assessment of Biodistribution and Clearance in In-Vivo Model

Compound 3 (15 mg) was dissolved in DMSO (25 μL, 0.6 g/mL) and injectedin male Sprague-Dawley rats. Whole blood samples were taken regularlyover a 24 hr period. Compound 3 fluorescent signal in the whole bloodsamples were measured by microplate analysis (excitation: 320 nm andemission: 540 nm). Urine samples were also analyzed for Compound 3fluorescent signal. K_(e)=0.044 hr⁻¹, T_(1/2(e)), T_(1/2(Total))=15.7hr.

Example 30 Visualizing Coating Coverage on Balloon Catheter

PTCA balloon catheters as received, slightly deployed and unwrapped weredip coated and sprayed in a solution of Compound 3 in 90:10 toluene:THFand dried in a 50° C. flow over overnight. The balloon catheter wasslightly deployed using a glass syringe and 18G tubing. Sprayed balloonswere coated with an EFD spray system with settings specific to Compound3. Coating was evaluated with a short wave UV lamp. The unwrappedballoon catheter had the most continuous coating, followed by theslightly inflated and the wrapped balloon.

Example 31 Coating Compound 1 on a Balloon Catheter and Evaluation ofCoating Pre and Post Deployment in Air

Compound 1 (1.0 g) was dissolved in THF, and kept at room temperatureuntil use. The solution was sprayed onto slightly deployed PTCA ballooncatheters using an EFD spray system with settings specific to Compound1, and dried in a 50° C. flow oven overnight. SEM analysis suggested athin, even coating pre and post deployment in air.

Example 32 Preparation of Compound 1+PTX, and PTX Loading of a CoatedBalloon Catheter

Compound 1 (0.4 g) and PTX (0.04 g-1.6 g) were dissolved in THF, andused immediately. Balloon catheters (3.0 mm×17 mm) were either sprayedor dip-coated. Sprayed balloons were coated with an EFD spray systemwith settings developed specifically for Compound 1. For dip coating,balloon catheters were secured in place with small clamps while thedipping solution was raised to a specified height using a scissor lifttable. Coated balloons were stripped in appropriate solvent overnight.PTX loading was measured using RP-HPLC with benzonitrile as the internalstandard. Loading was controlled by changing number of dips or sprays(ug/mm²): 0.2-6.0.

Example 33 Evaluation of Inflammatory Cell Response to Compounds 1, 2,5-11, 16-18, 24

Compounds 1, 2, 5-11, 24 were dissolved in THF or toluene, and were castinto 96 well polypropylene plates. The solvent was evaporated at roomtemperature for 24 hours, then placed in a 60° C. flow oven for 24hours, and finally dried under vacuum overnight. Compounds 16-18 weredissolved in toluene containing BPO initiator (1 wt % of Compounds 16-18mass). The toluene solution was cast into 96 well polypropylene platesand placed in a semi-enclosed chamber at room temperature for 1 day.Compounds 16-18 films were then cured for 12 hours in an N₂ purged 60°C. oven, and vacuum dried. For comparison purposes, films of SIBS and316 stainless steel inserts were added to the plates. The plates weresterilized under a UV lamp for 1 hour, after which each sample well washydrated with PBS. U937 monocyte-like cells (2.5×105 cells) were seededinto each well in the presence of PMA, and the plates were incubated at37° C. in a humid incubator for three days. Non-adherent cells wereremoved, and adherent U937 macrophages were enumerated using a CyQuantassay.

Example 34 Migration of HCAEC Through Membranes Coated with SelectedCompounds and 10 wt % PTX

Compound 1 (0.1 g) was dissolved in MeOH (0.5, 1, 2 and 4 mL), and thesesolutions (0.05 mL) were pipetted onto and wicked through a BD 8 μm PETmembrane insert. Compound 1 was also blended with PTX to form 1 and 10wt % solutions, and these were coated onto membranes. As a control, asolution of SIBS polymer of suitable concentration was coated ontomembranes. The resulting coated membranes were examined by SEM andporosity was confirmed by the passage of water through the membranes.Further, Compound 3 was coated using the same method, and fluorescence(Ex 320, Em 540 nm) was measured to confirm the presence of coating:(uncoated membrane)=3.5, (Compound 1)=0.6, (Compound 3)=28.2. HCAEC werecultured to third passage using media and supplements supplied by Lonza,and were starved in serum-free media overnight. Cells were lifted andre-suspended in 0.5% FBS media, and HCAEC were seeded (80 000 permembrane insert). The lower wells were filled with 20% FBS media. Thenegative control consisted of an uncoated membrane with 0.5% FBS mediain the lower well. The positive control consisted of an uncoatedmembrane with 20% FBS media in the lower well. After four hours ofincubation, the wells were lifted out, the inner membranes were scrubbedfree of cells, and the lower membrane surface was fixed and stained withDiffQuik. Images of the membranes were collected by microscopy, and cellmorphology characteristics and population were recorded.

The migration assay as described for the HCAEC was repeated with celllines from other species on all Compounds described in Examples 1, 5,7-11.

Example 35 Evaluation of Platelet and Fibrinogen Interaction with Filmsof Compounds 1, 16 and 17

Compound 1 was dissolved in toluene and stirred for 24 hours at roomtemperature. The solution was sprayed onto 4 cm×4 cm 316L stainlesssteel coupons using an EFD spray system with settings specific toCompound 1. The coupons were dried in a 50° C. flow oven for 20-24hours. Compounds 16 and 17 were dissolved in toluene containing BPOinitiator (1 wt % of Compounds 16 and 17 mass) and the solution was castinto 4 cm×4 cm PTFE wells (6 mL per well), and the PTFE casting platewas placed in a semi-enclosed chamber at room temperature for 1 day. TheCompound 16 and 17 films were then cured for 12 hours in a N₂ purged 60°C. oven. Human whole blood was obtained from healthy drug-freevolunteers and collected in centrifuge tubes with either acid citratedextrose anti-coagulant (6 parts ACD to 1 part blood) or low molecularweight heparin to a final concentration of 0.2 U/mL. Platelets fromblood collected with ACD were isolated by centrifugation and tagged with0.5 mCi/mL Na51Cr. Red blood cells were also isolated from the ACD wholeblood and washed. The Na51Cr tagged platelets and washed red blood cellswere combined with platelet poor plasma to give a final plateletconcentration of 250,000 platelets/μL and a 40% hematocrit. Finally,125I-fibrinogen was added to the whole blood suspension such that itrepresented approximately 2% of the total amount of fibrinogen. Plateletadhesion was measured from flowing whole blood in a cone-and-platedevice which produces laminar flow and a uniform rate of shear. Coatedcoupons and films were placed in the wells of the cone-and-plate devicewith 1.2 mL of the whole blood suspension containing Na51Cr plateletsand the assay was conducted for 15 minutes. The coupons and films werethen rinsed with fresh buffer and the radioactivity was measured with aγ counter and correlated to the number of adherent platelets (Na51Crplatelets) and adsorbed fibrinogen (125I-fibrinogen) based on theradioactivity of the original whole blood suspension. Compared to theuncoated stainless steel coupon, Compounds 1, 16 and 17 significantlyreduced platelet adhesion and fibrinogen adsorption.

Example 36 Evaluation of Protein Adhesion with Films of Compound 1

Films of Compound 1 used in Example 35 were also processed to evaluateprotein adhesion. Surfaces were rinsed with isotonic tris buffer andthen exposed to 2% sodium dodecyl sulfate for 24 hours to eluteproteins. SDS-PAGE gels were then performed. Protein bands were notvisible suggesting minimal protein adhesion.

Example 37 MEM Elution Assay—Cytotoxicity Assessment of Compounds 1, 2,5-11, 17 and 18

Compounds 1, 2, and 5-11 were weighed and incubated in MEM media at a 4g:20 mL ratio for 24 hours at 37° C. Films of Compounds 17 and 18 weretreated in the same fashion. L-929 mouse fibroblast cells were seededand incubated at 37° C. in 5% CO2 to obtain sub-confluent monolayers ofcells. The growth medium in triplicate cultures was replaced with MEMextract (2 mL). Triplicate cultures were also prepared as positive andnegative controls. Cell cultures were examined under microscope after 24hours to evaluate cellular characteristics and percent lysis. Under theconditions of this test, the MEM extracts showed no evidence of causingcell lysis or toxicity.

Example 38 Direct Contact Assay of Compound 1

The viability of HeLa epithelial cells in direct contact with testmaterials was used to assess the potential cytotoxicity of Compound 1.Samples of Compound 1 were solvent cast on agar-supported Supor filters.Subsequently, a monolayer of HeLa cells were cultured directly on thefilter, in the presence of MEM culture media. After 24 hours ofincubation, the Supor filter was rinsed and stained with succinicdehydrogenase. Viable cells were identified by a positive purple stainand cytotoxicity was determined by examining the stained filter for cellexclusion zones around the cast material, or a low cell density. Eachcytotoxicity assay included a positive and negative control.

Example 39 Dose Dependant Cytotoxicity of Compounds 24 and 18

Compounds 24 and 18 were dissolved in DMSO and added to MEM media atvarious concentrations. L-929 mouse fibroblast cells were seeded andincubated at 37° C. in 5% CO₂ to obtain sub-confluent monolayers ofcells. The growth medium in triplicate cultures was replaced withCompounds 24 and 18 containing MEM media. Triplicate cultures were alsoprepared as positive and negative controls. Cell viability was examinedafter 24 hour incubation by WST-1 assay at 1 mg/ml and reported as %viable compared to control. Compound 24=99.8% and Compound 18=96%.

Example 40 Compound 1, 5, 8, 9, 11, and 24 Compatibility with VariousTherapeutic Agents

Compounds 1, 5, 8, 9, and 11 were mixed with Troglitazone, C6-Ceramide,Cerivastatin, Prostaglandin E1, VEGF, Paclitaxel, Rapamycine andDexamethasone in appropriate solvent at various concentrations. Compound24 was also mixed with Paclitaxel, C6-Ceramide, Rapamycin, andIbuprofen. Solutions were drop-casted onto stainless steel coupons ornylon films and visually inspected macroscopically and microscopicallyfor phase separation and crystallization. Compounds 1, 5, 8, 9, 11, and24 were compatible with a variety of therapeutic agents.

Example 41 PTX Transfer to Cardiac Muscle from Coated Nylon Films

Compounds 2, 6, and 24 (500 mg)+PTX (214 mg) dissolved in THF weredrop-casted onto nylon 12 films and dried overnight in a 50° C. flowoven. Thin pieces of porcine cardiac muscle were soaked in porcine wholeblood. The coated nylon 12 films were then placed on top of the cardiacmuscle for up to 5 minutes. Transferred PTX was quantified by extractionof cardiac muscle in THF and supernatant analyzed by RP-HPLC withbenzonitrile as the internal standard. PTX transferred at 30 s, 1 min,and 5 min, respectively: Compound 2: 38.53 ng, 209.09 ng, 508.94 ng;Compound 6: 133.23 ng, 262.39 ng, 1041.07 ng; Compound 24: 1574.86 ng,3398.16 ng, 11890.32 ng.

Example 42 Ex Vivo Model of PTX Dosage Upon Balloon Deployment

Porcine hearts sourced from local commercial farm suppliers, wereharvested and perfused with saline. The drug eluting balloon catheterwas advanced into position, and the system was deployed. The locationwas marked, the balloon was withdrawn, and the segment was fullydissected from the myocardium. Analysis of drug content involved tissuehomogenization, solid phase extraction (Waters HLB SPE) of thepharmaceutical, and HPLC analysis. The pharmaceutical remaining on theballoon was solvent extracted and analyzed by HPLC.

Example 43 Retention of PTX on Balloon after Exposure to Blood

Balloon catheters were coated with Compound 24+PTX and dried at roomtemperature for 4 days. Coated balloon catheters were then exposed toanti-coagulated porcine blood for 5 minutes. The remaining coating onthe balloon catheter was extracted with acetonitrile and PTX quantifiedby RP-HPLC with benzonitrile as the internal standard. % PTX retained onballoon: 72.8%.

Example 44 PTX Release During Deployment in Blood

Balloon catheters were coated with Compound 24+PTX and dried at roomtemperature for 4 days. Coated balloon catheters were then exposed toanti-coagulated porcine blood for 4 minutes and then inflated and heldfor 1 minute. The remaining coating on the balloon catheter wasextracted with Acetonitrile and PTX quantified by RP-HPLC withbenzonitrile as the internal standard. % PTX released: 67.4%.

Example 45 Animal Study in Rabbit Model

Coated and non-coated balloons were included in the study. Briefly, acarotid arteriotomy was performed. The right common carotid artery wasisolated, a 5F introducer was placed and advanced, and a controlaortoiliofemoral angiogram was performed via a 4F angiographic catheterpositioned above aortic bifurcation. Heparin and lidocaine was injectedintra-arterially. Coated balloon and non-coated balloons were introducedunder fluoroscopic guidance and inflated according to study protocols.Based on the study design the treated vessel was explanted forquantitative analysis of the drug uptake. Methods for drug extractionand quantification were developed and established.

Example 46 Animal Study in Porcine Model

Coated balloon catheters with Compound 24 were inflated in porcinecoronary arteries (castrated male farm porcines, Sus scrofa domestica)or placed at the site of inflation, wrapped, for up to 1 minute. Eachanimal was given ASA (0.081 g) and Clopidogrel (0.075 g) by mouth dailyfor three days prior to treatment, and was fasted overnight before theprocedure. For surgical procedures, after sedation a marginal ear veinwas cannulated for infusion of intravenous fluids and medications. Theanimal was intubated for administration of anesthetic gases and placedon the catheterization table. Under sterile conditions, a vascularintroducer sheath was placed in the right carotid artery by surgical cutdown. Continuous hemodynamic monitoring and electrocardiographicmonitoring was maintained throughout the procedure. Using the guidecatheter as a calibration reference, the diameter of the vessel atreference sites proximal and distal to the intended site of implant, aswell as the target site diameter, was measured. The remaining coating onthe balloon catheter after the procedure was extracted with Acetonitrileand PTX quantified by RP-HPLC with benzonitrile as the internalstandard. % PTX released: Wrapped: 60.2; Inflated: 98.8.

Example 47 Assessment of Systemic Levels of Inflammatory Markers (CRP,MCP-1 and IL-6)

Blood was collected by venipuncture phlebotomy, in EDTA and dry tubesaccording to study protocols. The blood, in EDTA tubes was centrifugedat 3000 rpm for 15 minutes and the plasma was collected and stored at−20° C. Blood collected in dry tubes was left to clot at roomtemperature for 15 minutes and centrifuged at 3000 rpm for 10 minutes.Serum was then divided and stored. Quantification of CRP was performedon the serum samples using immunological agglutination. MCP-1 and IL-6were measured from plasma by ELISA colorimetric assay. Standard curvesfor MCP-1 and IL-6 were prepared with optical density measured at 450 nmwavelength. Results of mean CRP, MCP-1, and IL-6 were statisticallycompared at each time point using Student's t-tests.

Example 48 Assessment of Therapeutic Retention of Balloon Coating UnderFlow Condition (Blood Loop Model)

Anti-coagulated whole porcine blood at 37° C. was pumped by aperistaltic pump through silicone tubing connections. The pump flow ratewas set similar to the rate of blood through the coronary arteries (71.4mL/min). A coated balloon catheter with compound 1 or 24 was placed inthe middle of the blood flow for 1 minute. PTX remaining on the ballooncatheter was measured by stripping the coating and quantified usingRP-HPLC with benzonitrile as the internal standard. % PTX remaining:Compound 1: 94.4%, Compound 24: 52.2%.

Example 49 Assessment of Anti-Fouling Properties of Balloon Coating

Compound 1 (125 mg) was dissolved in THF (1 mL) and drop casted onto aNylon film. The Nylon film and Nylon film coated with Compound 1 werequalitatively evaluated for protein adsorption using Coomassie BrilliantBlue R dye, (CBB) after incubating in 1 mL of 500 mg/mL BSA for 40minutes. Negative controls (without BSA incubation) were also evaluated.After rinsing with distilled water to remove non-adherent protein, 1 mLof 0.25% CBB reagent was added to all samples and incubated for 40minutes. All samples were rinsed with distilled water and dried. It wasshown that BSA-incubated Nylon films coated with Compound 1 showed lessprotein adsorption (dark blue deposition) than BSA-incubated Nylon filmsalone (FIG. 3).

Example 50 Assessment of Drug Shielding Effect and Adhesion on Nylon 12Film Sheet

Compounds 1, 7, and 14 (200 mg/mL) were dissolved in THF. PTX was addedto each solution to make a 25 mg/mL solution. Nylon 12 film sheets werecut 1×1 cm size, blend solution was drop cast on the film sheet, driedin a 50° C. flow oven for 1 day. PTX alone was prepared the same way andused as the control. PBS pH 7.4 was pre-warmed to 37° C. Test articlesand control articles were incubated in media (4 mL) at 37° C. for 10,30, 60 and 120 minutes. At the end of each time point, media wasexchanged and at the end of the study, the films were stripped withorganic solvent, centrifuged, the supernatant collected, and solventdried overnight at 60° C. The assessment of the drug shielding effectwas analyzed by RP-HPLC with benzonitrile as the internal standard. 10minute PTX release in PBS (ng/mL): Compound 1: 107.6, Compound 7: 79.7,Compound 14: 15.4, PTX alone: 651. The assessment of oligofluoroadhesion on film surface was done by NMR. A calibration curve for eachcompound was generated by NMR. Stripped coating was re-suspended inCDCl₃ (1 mL) and NMR was performed. Quantity of remaining material wasback calculated from NMR integration area. Percent remaining materialafter 120 minute incubation in PBS: Compound 1: 82.1, Compound 7: 85.5.Similar assessment of drug shielding on films was done with porcinewhole blood. 10 minute PTX release in blood (%): Compound 1: 28.8,Compound 7: 34.0, Compound 14: 57.4, PTX alone: 75.6.

Example 51 Assessment of Therapeutic Retention of Balloon Coating in aRabbit Model

Angioplasty was performed normally as in Example 42 with coated ballooncatheters. Upon reaching the treatment site, balloon catheter wasretracted without deployment. The coating integrity was examined usingSEM at the end of study. PTX concentration remained in the coating wasmeasured by stripping the coating and quantified using the followinganalytical methods: high pressure liquid chromatography (HPLC) and gelpermeation chromatography (GPC).

Example 52 Oligofluoro as Solubilizing Agent

Several water insoluble drugs, paclitaxel (PTX), rapamycin, andibuprofen were complexed with Compound 24 at 4 wt %. Coating was made onnylon film by drop casting method. Control films with drug coated onlywas also prepared in a same manner. Coated nylon films were incubated inwater for 24 hours to measure drug release. Percentage drug released inwater: Compound 24+PTX=94, PTX control=11; Compound 24+rapamycin=79,rapamycin control=4; Compound 24+ibuprofen=80, ibuprofen control=40.

Balloon catheters were coated with Compound 24+PTX and non-fluorinateddiol+PTX. Balloon catheters were stripped in water to evaluate coatingsolubility in aqueous solution. PTX measurement from stripped coating inwater is the following: Compound 24+PTX=680 μg; non-fluorinateddiol+PTX=26 μg.

Example 53 Coating Characterization on Surface of Balloon Catheter

Balloon catheters were coated according to the established protocol(Compound 24+PTX). Coating characterization was done by XPS for wrappedcoated balloon, deployed coated balloon, and wrapped uncoated balloon asa control. Surface characterization was done at 4 different points alonga single line for each balloon. Percentage of surface fluorine onuncoated balloon: 0.44, 0.26, 0.36, 0.52; on coated balloon (wrapped):31.39, 30.62, 30.71, 33.78; on coated balloon (deployed): 36.61, 32.71,32.93, 31.21. Surface characterization suggests a continuous coatingthroughout the surface of the balloon.

Example 54 High PTX Loading on Balloon Coating

Compound 1 and 24 and non-fluorinated diol were mixed with PTX. Ballooncatheters were coated with these solutions and dried according toestablished method. Coatings were stripped with organic solvent and PTXwas measured by HPLC. PTX measurements in Compound 1, Compound 24, andnon-fluorinated diol were 961 μg, 713 μg, 466 μg, respectively.

Example 55 Particle Size Analysis

Balloon catheters were coated with Compound 24 and dried at roomtemperature for 4 days. Coated balloon catheters were exposed to PBS for1 minute and then inflated and held for 1 minute. Uncoated ballooncatheters were used as control. PBS solutions were analyzed forparticles using a HIAC Royco Particle Counter with USP33-NF28,Supplement 1, <789><788> as a general guideline. All samples passed theUSP <788> limits for SVI (<100 mL). % Total Differential Particle Counts(5 μm, 10 μm, 25 μm): Control: 79.8, 14.36, 0.11; Compound 24: 81.2,13.1, 0.32.

Example 56 Acute Systemic Toxicity

A single-dose systemic injection of Compound 24 in PBS (12 mg/mL) wasgiven to 5 Albino Swiss mice and toxicity observed over a 72 hourperiod. Mice were dosed at 50 mL/kg at an injection rate of ˜0.1 mL/sec.Observations for mortality and signs of pharmacological and/ortoxicological effects were made immediately post-injection and at 4, 24,48 and 72 hours post-injection. No clinical signs of toxicity wereobserved during the study period.

Example 57 Double Coating

Nylon12 films were first treated with a selection of Compounds, and thencoated with Compounds containing PTX. PTX release in Tween Buffer for 60minutes (% Release): Compound 1 alone: 0.7%, Compound 11 and Compound 1:76%.

Example 58 Assessment of Drug Shielding Effect and Adhesion on BalloonCatheters

Balloon catheters were coated with either Compound 1 (12.5 mg Compound1, 50 mg PTX, 1 mL THF) or a urea formulation (16 mg urea, 52 mg PTX,936 μL THF, 104 μL water). Balloon catheters were incubated in PBS for 5minutes. % PTX release: Compound 1: 0.35, urea: 58.02.

Example 59 Temperature Dependence on Drug Release (PTX Release at RoomTemperature and 37° C.)

Compounds 1, 6, 10 were mixed with PTX at 50 wt % in appropriatesolvents. PTX containing solution was drop casted on nylon films anddried. Films were incubated in 4 ml, PBS at room temperature (RT) and at37° C. for 1 minute. Coated control films were prepared and stripped in4 mL organic solvent. PTX release was measured by HPLC. PTX release atRT and 37° C. for Compound 1, 6, and 10: 4 ng and 417 ng, 39 ng and 543ng, 59 ng and 188 ng, respectively.

Example 60 Solvent Free System of Compound 24+PTX

Several compounds were combined with PTX in the previous examples usingvarious solvents. Compound 24 was also combined with PTX using thesemethods as well as combined in a solvent free system. Compound 24 (75mg) was warmed in a 60° C. flow oven, added to PTX (3 mg) and mixed. Nophase separation was seen macroscopically or microscopically after 24hours at room temperature.

Other Embodiments

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each independent publication or patent application was specificallyand individually indicated to be incorporated by reference.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe claims.

Other embodiments are within the claims.

What is claimed is: 1-93. (canceled)
 94. A method for delivering abiologically active agent to a site in a vessel, said method comprising:(i) providing a balloon catheter having a surface with a coatingthereon, said coating comprising said biologically active agent and anoligofluorinated oligomer comprising a hard segment, a soft segment, anda polyfluoroorgano group; (ii) inserting said balloon catheter into saidvessel; (iii) positioning said balloon catheter near said site; (iv)delivering said biologically active agent to a wall of said vessel bydeploying said balloon catheter into a deformed and expandedconfiguration to contact said wall; and (v) removing said ballooncatheter from said vessel with at least a portion of said coatingremaining at said site in the absence of an implanted medical device;wherein said biologically active agent is an antiproliferative agent ora rapamycin macrolide.
 95. (canceled)
 96. A method for inhibitingrestenosis at a site in a vessel, said method comprising: (i) providinga balloon catheter having a surface with a coating thereon, said coatingcomprising a biologically active agent and an oligofluorinated oligomercomprising a hard segment, a soft segment, and a polyfluoroorgano group;(ii) inserting said balloon catheter into said vessel; (iii) positioningsaid balloon catheter near said site; (iv) applying said biologicallyactive agent to a wall of said vessel by deploying said balloon catheterinto a deformed and expanded configuration to contact said wall; and (v)removing said balloon catheter from said vessel with at least a portionof said coating remaining at said site in the absence of an implantedmedical device; wherein said biologically active agent is anantiproliferative agent or a rapamycin macrolide.
 97. The method ofclaim 94, wherein said vessel is a bifurcated vessel. 98.-102.(canceled)
 103. The method of claim 94, wherein said coating on thesurface of said balloon catheter has a thickness of from 0.01 to 250microns.
 104. The method of claim 94, wherein said coating consists ofcomponents having a molecular weight of from 1 kDa to 60 kDa.
 105. Themethod of claim 94, wherein said oligofluorinated oligomer has atheoretical molecular weight of 1 kDa to 30 kDa.
 106. The method ofclaim 94, wherein said coating comprises from 0.5 to 50% (w/w) saidbiologically active.
 107. The method of claim 94, wherein said vessel isa blood vessel.
 108. The method of claim 94, wherein from 5 to 55% (w/w)said biologically active agent is delivered to said vessel.
 109. Themethod of claim 94, wherein said coating comprises a molar ratio of saidoligofluorinated oligomer to said biologically active agent of from 20:1to 1:20.
 110. The method of claim 94, wherein said coating has a glasstransition of from −80 to 40° C.
 111. The method of claim 94, whereinsaid coating has a tack of from 1.0 to 200 g.
 112. The method of claim94, wherein said coating has a viscosity of from 0.04 to 130 cps. 113.The method of claim 94, wherein said coating has a contact anglehysteresis of the surface of from 20-120°.
 114. The method of claim 94,wherein said hard segment is formed from lysine diisocyanate orhexamethylene diisocyanate.
 115. The method of claim 94, wherein softsegment is an oligo selected from the group consisting of polyurethane,polyurea, polyamides, polyalkylene oxide, polycarbonate, polyester,polylactone, polysilicone, polyethersulfone, polyolefin, polyvinyl,polypeptide, and polysaccharide.
 116. The method of claim 94, whereinsaid polyfluoroorgano group is a polyfluoroalkyl having a molecularweight of between 100 Da and 1,500 Da.
 117. The method of claim 94,wherein said polyfluoroorgano group is a group having the formulaCH_(m)F_((3-m))(CF₂)_(r)CH₂CH₂— orCH_(m)F_((3-m))(CF₂)_(s)(CH₂CH₂O)_(χ)—, wherein m is 0, 1, 2, or 3; χ isan integer between 1-10; r is an integer between 2-20; and s is aninteger between 1-20.
 118. The method of claim 94, wherein saidpolyfluoroorgano group is formed from 1H,1H,2H,2H-perfluoro-1-decanol;1H,1H,2H,2H-perfluoro-1-octanol; 1H,1H,5H-perfluoro-1-pentanol; or1H,1H, perfluoro-1-butanol, or a mixture thereof.
 119. The method ofclaim 94, wherein said oligofluorinated oligomer comprises a hardsegment, a soft segment, and polyfluoroorgano group, wherein saidoligofluorinated oligomer comprises from 5 to 80% (w/w) of said hardsegment, from 10 to 90% (w/w) of said soft segment, and from 5 to 80%(w/w) of said polyfluoroorgano group.
 120. The method of claim 94,wherein said biologically active agent is an antiproliferative agentselected from the group consisting of methotrexate, trimetrexate,gemcitabine, vinblastine, vincristine, etoposide, teniposide, topotecan,irinotecan, camptothecin, 9-aminocamptothecin, paclitaxel, docetaxel,daunorubicin, doxorubicin, dactinomycin, idarubincin, bleomycin, andtamoxifen.
 121. A balloon catheter having a surface with a coatingthereon, said coating comprising a biologically active agent and anoligofluorinated oligomer comprising a hard segment, a soft segment, anda polyfluoroorgano group; wherein said biologically active agent is anantiproliferative agent or a rapamycin macrolide.